Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mo:1](=O)(=O)=[O:2].C.C1(N)N=C(N)N=C(N)N=1.C1(N)N=C(N)N=C(N)N=1.[C:24]([O-:29])(=[O:28])[C:25]([O-:27])=[O:26].[Cu+2:30].C1C(=O)N(Br)C(=O)C1>>[Mo:1]=[O:2].[C:24]([O-:29])(=[O:28])[C:25]([O-:27])=[O:26].[Cu+2:30]
Reactant: O=[Mo](=O)=O
Agent: [Cu+2]
Agent: Nc1nc(N)nc(N)n1
Agent: O=C([O-])C(=O)[O-]
Product: O=[Mo]

Procedure:
When molybdenum trioxide is substituted for the melamine molybdate in combination with the copper oxalate in the above compound, no practical synergism is noted with this combination. For example, in the flaming mode NBS smoke test Dm /g values of about 23 (58.8% smoke reduction relative to the standard compound of Example I) were obtained with ratios of 1.0 molybdenum oxide and 4.0 copper oxalate, 2.0 molybdenum oxide and 3.0 copper oxalate, 3.0 molybdenum oxide and 2.0 copper oxalate, 4.0 molybdenum oxide and 1.0 copper oxalate. In contrast, it should be noted that when 1.0 copper oxalate and 4.0 melamine molybdate were used in the same compound the Dm /g was 19.08 with a smoke reduction of 65.1%, and with 4.0 copper oxalate and 1.0 melamine molybdate the Dm /g was 19.92 and a 64.38% smoke reduction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[C:19]1([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH2:16][N:15]([C:31]([C:26]4[C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:32])[CH2:14][CH:13]3[CH2:12]2)[N:4]=1
Reactant: O=C(O)c1ncccc1-c1ccccc1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4ncccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 39 and 3-phenyl-pyridine-2-carboxylic acid. MS (ESI): mass calculated for C24H25N5O3, 431.50; m/z found 432.3 [M+H]+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[CH:20][C:15]=2[O:14][CH2:13]1>C(Cl)Cl>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([CH3:25])([CH3:24])[CH:22]=[O:23])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CC(C)(CO)c1ccc2c(c1)OCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3A° molecular sieves (6.5 g) in CH2Cl2 (15 mL) was stirred at room temperature for 30 minutes and then PCC (pyridinium chlorochromate) (2 g) was added. To this PCC suspension, a solution of Compound H (1 g, 5.15 mmol) in dry CH2Cl2 (15 mL) was added dropwise and was stirred at room temperature for 3.5 hours.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][OH:8].[C:9](=S)=[S:10].Cl>C(O)C.O>[OH:8][CH2:7][CH2:6][N:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:9]1=[S:10]
Reactant: NCCCNCCO
Reactant: S=C=S
Agent: Cl
Solvent: O
Solvent: CCO
Product: OCCN1CCCNC1=S

Procedure:
2-(3-Aminopropylamino)ethanol (118 ml) is dissolved in 1:1 ethyl alcohol-water (340 ml) and heated to 40°-50° C. Carbon disulfide (60 ml) is added dropwise over a period of about 15 minutes. An exothermic reaction occurs after about half of the amount of carbon disulfide is added. After the addition of all the carbon disulfide, the mixture is refluxed for about 1 hour. Concentrated hydrochloric acid (8 ml) is then added, and the reaction mixture is refluxed overnight. After cooling in an ice bath, the crystalline solid which separates is filtered, washed with isopropyl alcohol and t-butyl methyl ether, and dried to give 129-4 g of 1-(2-hydroxyethyl)-3,4,5,6-tetrahydropyrimidine-2-thione, melting point 112°-114° C.
Reaction SMILES: [Ni:1].C[OH:3].[CH2:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:5]1([OH:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Ni:1].[CH3:4][OH:11]
Reactant: OCc1ccccc1
Agent: [Ni]
Solvent: CO
Solvent: c1ccccc1
Product: Oc1ccccc1

Procedure:
[2,2'-thiobis-(4-t-octyl-phenolato)]-benzyl alcohol Nickel II, NiTBP.C6H5OH was prepared as follows: p [2,2'-thiobis-(4-t-octylphenolato)]-2-propanol nickel II prepared as described in Example 4 (83.9 g) was dissolved in benzene (250 ml) and benzyl alcohol (16.2 g) was then added. The resulting solution was heated and refluxed for 1 hr. The displaced 2-propanol and most of the benzene solvent was then removed by distillation and the remainder by rotary evaporation. The complex[2,2'-thiobis-(4-t-octylphenolato)]benzyl alcohol nickel II was thus obtained as a green solid which softened at 150° C., melted partially at 210° C. and was completely fused at 260° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=O)[CH2:8][O:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: O=C1COc2nccc(Cl)c2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccnc2c1NCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-chloro-1H-pyrido[2,3-b][1,4]oxazin-2-one (600 mg, 3.25 mmol) was dissolved in anhydrous tetrahydrofuran (16 ml) under nitrogen atmosphere, and then cooled to 0□. 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (6.5 ml, 6.50 mmol) was added thereto dropwise, and then stirred for 30 minutes. The reaction temperature was raised to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0□ again, and water (0.26 ml), 10% sodium hydroxide solution (0.52 ml) and water (0.78 ml) were added thereto dropwise in this order, and then stirred vigorously at room temperature for 1 hour. The formed solid was filtered and washed with excess ethyl acetate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:9]1=[O:21]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:9]1=[O:21]
Reactant: C[C@H]1[C@@H](C/C=C/c2cccs2)C(=O)N1OC1CCCCO1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1[C@@H](CCCc2cccs2)C(=O)N1OC1CCCCO1
Reaction time: 72 h
Yield: 99.3 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-(thiophene-2-yl)-2-propene-1-yl)-4-methylazetidin-2-one (130 mg, 0.423 mmol) in 3 mL of methanol is treated with 20 mg of 5% palladium on barium sulfate. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 72 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(thiophene-2-yl)-1-propyl)-4-methylazetidin-2-one as an oil (130 mg, 100% yield).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[C:19]1[C:20](=[O:36])[N:21]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][C:26]=2[CH3:35])[CH:22]=[CH:23][CH:24]=1>O1CCOCC1>[CH3:35][C:26]1[CH:27]=[C:28]([N+:32]([O-:34])=[O:33])[CH:29]=[C:30]([CH3:31])[C:25]=1[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])[C:20]1=[O:36]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(Br)c1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Temperature: 57.5 °C
Reaction time: 1 h

Procedure:
Under argon, 42.5 g (379 mmol) of potassium tert-butylate were suspended in 530 ml of dioxane and heated to 55-60° C. At this temperature, a solution of 60.7 g (379 mmol) of diethyl malonate in 100 ml of dioxane was added over 20 min. When the addition was complete, the reaction mixture was stirred for 1 h at 60° C. 6.72 g (21.7 mmol) of bis(2-pyridinecarboxylato)copper(II) complex were then added, as were 35.0 g (108 mmol) of 3-bromo-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one. The reaction mixture was heated at reflux for 8 h and then stirred overnight at RT. Filtering off the liquid from the solid with suction was carried out, followed by after-washing with dioxane, and the filtrate was evaporated to 250 g on a rotary evaporator. The crude solution was further reacted without purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][C:4]1([NH:15][C:16](=[O:19])[O:17][CH3:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH:3]1[CH2:5][C:4]1([NH:15][C:16]([O:17][CH3:18])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (1SR,2RS)-2-(hydroxymethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (intermediate B7a) (3.5 g, 13.1 mmol, Eq: 1.00) in dichloromethane (20 ml) at 0° C. was added triethylamine (2.66 g, 3.66 ml, 26.3 mmol, Eq: 2.00) followed by dropwise addition of methanesulfonyl chloride (2.26 g, 1.54 ml, 19.7 mmol, Eq: 1.50) and the mixture was stirred at 0° C. for 2 h. Poured into ice cold 1 M HCl-sol., extracted with tert-butyl methyl ether, washed organic layer with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a yellow oil. MS (ISP): m/z=362.1 [(M+NH4)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:16])[CH3:15]
Reactant: CC(=O)c1ccccc1
Reactant: Brc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccccc1Br
Reaction time: 0 h
Yield: 81 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with acetophenone (0.65 M) in THF (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The solution was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=75 cm) was 3.46 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, 1-(2-bromophenyl)-1-phenylethanol (GC retention time: 23.5 min) was obtained in 81% yield. 1H NMR (400 MHz, CDCl3) δ: 1.95 (s, 3H), 3.49 (s, 1H), 7.16 (dt, J=7.6, 1.6 Hz, 1H), 7.20-7.30 (m, 5H), 7.38 (dt, J=7.6, 1.2 Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.80 (dd, J=7.6, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 30.4, 77.4, 122.2, 125.4, 126.7, 127.2, 128.0, 128.3, 129.0, 134.7, 144.7, 147.4. HRMS (EI) m/z: calcd. for C14H13BrO 276.0150, found 276.0155.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)=[O:3].[Mn]([O-])(=O)(=O)=[O:25].[K+]>O>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)(=[O:25])=[O:3]
Reactant: CS(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 8 h

Procedure:
A stirred solution of 0.64 g (1.98 mmoles) of 2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]pyrrolo[1,2-a]imidazole of Example 4 in water was treated dropwise over 45 minutes with an aqueous solution of 0.209 g (1.32 mmoles) of potassium permanganate. After stirring overnight, the suspension was extracted with methylene chloride. The organic phase was dried over anhydrous potassium carbonate and stripped in vacuo. The residue flash chromatographed in silica eluting with 2 to 4% methanol in chloroform. The solvent was removed in vacuo and the residue recrystallized from ethyl acetate to afford the desired titled compound, mp 222.5°-224° C. 1H NMR (250 MHz, CDCl3) δ 8.62 (2H,d), 7.85 (2H,d), 7.72 (2H,d), 7.26 (2H,d), 4.05 (2H,t), 3.05(s) superimposed upon 3.03(t) (5H total), 2.70 (2H,q).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].[CH2:33](I)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(O)CCC>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCI
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(O)cc4)cn3)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(OCCCCCC)cc4)cn3)cc2C1
Temperature: 0 °C
Yield: 76 %

Procedure:
0.25 g (0.62 mM) of 2-octyl-5-[5-(4-hydroxyphenyl)pyrimidine-2-yl]indan, 0.07 g of 85% -potassium hydroxide, 0.2 ml of hexyl iodide and 5 ml of n-butanol were placed in a 20 ml-round bottomed flask, followed by heat-refluxing for 3.5 hours under stirring. After the reaction, the reaction mixture was poured into ice water. The resultant insoluble matter was recovered by filtration and dissolved in toluene, followed by washing with 3%-sodium thiosulfate aqueous solution. The water layer was subjected to extraction with toluene and the resultant toluene layer was added to the organic layer, followed by washing with saturated common salt aqueous solution, drying with anhydrous sodium sulfate and distilling-off of the solvent. The resultant crude product was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.23 g of 2-octyl-5-[5-(4-hexyloxyphenyl)pyrimidine-2-yl]indan (Yield: 76.0%). ##STR139##
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30].CO.[CH3:38][Si](C=[N+]=[N-])(C)C>O1CCCC1>[O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:20][CH:21]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([O:31][CH3:38])=[O:30]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.5 h

Procedure:
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzoic acid (Example 611, 30 mg, 0.065 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL) and treated with (trimethylsilyl)diazomethane (0.065 mL, 2 M diethyl ether solution, 0.13 mmol, 2 equiv). After stirring for 30 minutes, the mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.15 (1H s), 8.46 (1H, d, J=2.5 Hz), 8.21 (1H, dd, J=7.8, 1.4 Hz), 7.83 (2H, d, J=8.8 Hz), 7.79 (1H, m), 7.77 (1H, d, J=2.3 Hz), 7.73-7.61 (3H, m), 7.56 (1H, t, J=7.7 Hz), 7.46 (2H, d, 8.7 Hz), 7.41 (1H, td, J=7.7, 1.1 Hz), 6.53 (1H, dd, J=2.4, 1.8 Hz), 5.77 (2H, s), 3.67 (3H, s) ppm; low resolution mass spectrometry (ES+) m/z 476.0 [(M+H)+; calculated for C28H22N5O3: 476.2].
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8].[Li+].[BH4-]>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])[NH:11][C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](CCC(F)(F)F)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)CCC(F)(F)F)OCc1ccccc1

Procedure:
(2S)-2-Benzyloxycarbonylamino-5,5,5-trifluoropentanoic acid methyl ester from Step 2 was dissolved in dry THF (400 mL). A solution of LiBH4 (2.11 g in 100 mL of dry THF) was added dropwise with stirring and the solution was allowed to stir at ambient temperature overnight. The reaction mixture was concentrated by rotary evaporation and 400 mL of water was added. The pH was then adjusted to pH 2 by addition of concentrated HCl and then the product was extracted into ethyl acetate. The organic phase was washed two times with water, dried with MgSO4, filtered, and concentrated by rotary evaporation to yield crude (S)-(4,4,4-trifluoro-1-hydroxymethyl-butyl)-carbamic acid benzyl ester.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[OH:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:1]1
Reactant: ClCC1CO1
Reactant: OC1CCc2ccccc2S1
Product: c1ccc2c(c1)CCC(OCC1CO1)S2
Yield: 65000 %

Procedure:
The procedure of Step A of Example 1 is followed, starting from 1.72 g (10.34 mmol) of thiochromanol and 7.653 g (82.72 mmol) of epichlorohydrin. 1.5 g (6,721 mmol) of 2,3-epoxypropoxythiochroman are obtained.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[OH:26])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[C:29](OCC)(=O)C>CN(C=O)C>[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[O:26][CH3:29])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.04 g, 1.0 mmol) is suspended in DMF (10 ml), and thereto is added 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62 mmo) obtained in Example 30 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added methyl iodide (0.06 ml, 1.0 mmol) under ice-cooling, and the mixture is stirred for 1 0 minutes. To the reaction solution is added ethyl acetate (50 ml), and the mixture is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol), and recrystallized from isopropyl ether to give the title compound (0.09 g) as colorless crystals, m.p. 101-102° C.
Reaction SMILES: CN([CH:4]=[N:5][C:6]([C:8]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=O)C.[CH3:29][NH:30][NH2:31].C(O)(=O)C.ClCCl>O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:29][N:30]1[C:6]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:16][CH:15]=3)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[N:5][CH:4]=[N:31]1
Reactant: CNN
Reactant: CN(C)C=NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Cn1ncnc1C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 100 °C
Yield: 19.9 %

Procedure:
N-[(dimethylamino)methylene]-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide (0.34 g, 0.88 mmol), methyl hydrazine (0.116 mL, 2.19 mmol) and acetic acid (1 mL) were combined and heated at 100° C. for 2 hours. The reaction mixture was diluted with water (10 mL), solid sodium carbonate was added until the mixture was pH9. Dichloromethane (2×50 mL) was used to extract. The combined organics were dried over sodium sulphate, filtered and concentrated in vacuo to provide a yellow oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 90:10:1) to produce the title compound (0.065 g, 20%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.83-1.93 (m, 4H), 2.05-2.16 (m, 2H), 2.30 (m, 2H), 2.48 (m, 2H), 2.60-2.85 (m, 6H), 3.37 (s, 3H), 3.80 (m, 2H), 3.90 (m, 2H), 4.0 (t, 2H), 6.85 (d, 2H), 7.07 (d, 2H), 7.88 (s, 1H). HRMS ESI+ m/z 371.2434 [MH]+.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[Li]CCCC.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:17]#[N:18])[CH3:12].[BH4-].[Na+].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O1CCCC1.O>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:17]([NH2:18])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:12]
Reactant: CS(C)(=O)=O
Reactant: CCOc1cc(C#N)ccc1OC
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Temperature: 7.5 °C
Reaction time: 1.33 h
Yield: 70.5 %

Procedure:
Dimethylsulfone (14.1 g, 150 mmoles, from Aldrich Chemicals) and tetrahydrofuran (55 ml, from Aldrich Chemicals) were charged to a three-necked RBF at room temperature. The mixture was cooled to 5-10° C. n-BuLi (55 ml of 2.5M solution in hexanes, from Aldrich Chemicals) was added to the flask at a rate such that the reaction mixture was maintained at 5-10° C. A line rinse with 11 ml tetrahydrofuran followed. The mixture was stirred at 0-5° C. for 80 minutes. 3-Ethoxy-4-methoxybenzonitrile (22.2 g, 125 mmoles, in 45 ml tetrahydrofuran) was then charged to the flask at a rate such that the reaction mixture was maintained at 0-5° C. A line rinse with 11 ml tetrahydrofuran followed. The mixture was stirred at 0-5° C. for another 10-15 minutes. After warming to room temperature, the reaction mixture was stirred for another 1.5-2 hours and then transferred to a 1 L three-necked RBF containing a suspension of NaBH4 (6.1 g, 163 mmoles, from Acros) in 90 ml of tetrahydrofuran maintained at −10-0° C. A line rinse with 11 ml tetrahydrofuran followed. The reaction mixture was stirred at 0-5° C. for 30 minutes. TFA (43.3 ml, 563 mmoles, from Aldrich Chemicals) was charged to the flask at a rate such that the reaction mixture was maintained at 0-5° C. The mixture was stirred at 0-5° C. for 40 minutes and an additional 15 hours at ambient temperature. The mixture was then charged with 22.3 ml of DI water over 5 minutes at 15-20° C. The mixture was stirred at ambient temperature for 4 hours. Aq. NaOH (10N, 40 ml) was charged to the flask over 10-15 minutes at 45-50° C. The mixture was stirred at 45-50° C. for 2 hours, at 60° C. for 1.5 hours, at ambient overnight and 0-5° C. for 75 minutes. The mixture was clarified at 0-5° C. and the filtrate was concentrated on a Rotovap. The residual material was charged with DI water (110 ml) and Reagent alcohol (110 ml) and stirred at 0-5° C. for 2 hours. The mixture was filtered under vacuum, and the filtered solid was washed with cold Reagent alcohol (3×22 ml) followed by DI water until pH of the wash reached about 8. The solid was air dried, yielding 24.1 g (70.5%) of 2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-eth-2-ylamine (HPLC indicated 96.78% purity by peak area).