Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH:4]=[C:5]([CH3:8])[C:6]#[CH:7])[CH3:3].[CH:10](=[O:14])[CH:11]([CH3:13])[CH3:12].[Cl-].[NH4+]>C1C=CC=CC=1>[CH3:1][C:2]([OH:9])([CH:4]=[C:5]([CH3:8])[C:6]#[C:7][CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])[CH3:3]
Reactant: C#CC(C)=CC(C)(C)O
Reactant: CC(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: CC(C#CC(O)C(C)C)=CC(C)(C)O
Temperature: 10 °C
Reaction time: 3 h
Yield: 108.1 %

Procedure:
There are then added 150 ml of dry benzene and subsequently, while stirring and at a temperature between 30° C and 40° C, a solution of 55.9 g (0.45 mol) of 2,4-dimethyl-hex-3-en-5-yn-2-ol in 100 ml of dry benzene. After the addition, the mixture is held for 3 hours at 50° C and then cooled to 10° C. There is then added, within 1 hour at a temperature between 10° C and 20° C, a solution of 31.3 g (0.435 mol) of isobutyraldehyde in 100 ml of benzene. The mixture is left to stand for 12 hours at room temperature and then added with stirring to a solution of 40 g of ammonium chloride in 200 ml of ice-water. In order to facilitate separation of the phases, 53 ml of glacial acetic acid are added. The organic phase is separated and the aqueous layer extracted twice with ether. The combined extracts are washed neutral with a saturated sodium bicarbonate solution and a saturated sodium chloride solution and, after the addition of a small amount of hydroquinone, dried over sodium sulphate. After evaporation of the solvent (<40° C), there are obtained 92.3 g of crude 2,4,8-trimethyl-non-3-en-5-yne-2,7-diol which are immediately hydrogenated as follows: To a 1 liter magnetically stirred autoclave having built-in cooling spirals, there are added 92.3 g of crude 2,4,8-trimethyl-non-3-en-5-yne-2,7-diol, 5 g of Raney nickel, 0.5 g of Raney nickel, 0.5 g of anhydrous sodium carbonate and 125 ml of absolute methanol. The mixture is first hydrogenated while cooling with water at a pressure of ca 8 atmospheres. After the initial strongly exothermic reaction has ended, the mixture is hydrogenated up to complete saturation at 30 atmospheres of hydrogen and 80° C. After cooling, the catalyst is filtered off from the mixture, the alcohol removed on a rotary evaporator and the residue distilled over a small amount of sodium carbonate. There are thus obtained 70.6 g (74%) of 2,4,8-trimethyl-nona-2,7-diol of boiling point 130°-133° C/5 mm Hg; nD20 = 1.4600.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:19][C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:22][CH:21]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc(C(=O)OC(C)(C)C)cc3)C2=O)cc1

Procedure:
The title compound 28p was prepared from compound 2 (75 mg, 0.30 mmol), tert-butyl 4-(bromomethyl)benzoate (106 mg, 0.39 mmol) and potassium carbonate (83 mg, 0.60 mmol) in a manner similar to that described for 28d in 96.4% (127 mg) yield as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].[NH2:23][C@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[CH2:25][C:26]([O:28][CH3:29])=[O:27]>ClCCl.C(N(CC)C(C)C)(C)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][C@@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[NH:23][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1
Reactant: COC(=O)C[C@H](N)c1ccccc1Cl
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1Cl
Yield: 77.9 %

Procedure:
200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 130 mg of methyl(S)-3-amino-3-(2-chlorophenyl)propionate were dissolved in 5 ml of dichloromethane and 0.52 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 20 ml of dichloromethane and washed repeatedly with 20 ml of 25% aqueous ammonia solution, until the organic phase was colorless. The organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (191 mg) with a molecular weight of 402.9 g/mol (C17H23ClN2O5S); MS (ESI): m/e=403 (M+H+).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11]1>>[CH3:8][N:9]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11]1)[C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6]
Reactant: CNC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: O=C(Cl)C1CCC1
Product: CN(C(=O)C1CCC1)C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from cyclobutane carbonyl chloride and (3-methylamino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 378/380 (MH+); HPLC Rf: 4.71 min.; HPLC purity 98%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]1[O:21][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Ni].O1CCOCC1>[OH:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C1OC1c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
A mixture of ethyl-2,3-epoxy-3-(4benzyloxyphenyl)propionate of the formula (9) (125 g) obtained according to the procedure described in step (ii) above, Raney Nickel (12.5 g) and 1,4-dioxane (750 ml) was hydrogenated at room temperature at 30-40 psi of hydrogen pressure for a period of 8-10 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the solvent was removed under reduced pressure to afford the title compound of the formula (10) (100-105 g, 80-83%).
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([NH:20][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCN
Reactant: COC(=O)c1ccccc1O
Product: CCCCCCCCNC(=O)c1ccccc1O

Procedure:
N-octyl salicylic acid amide was prepared, using the process described in Example 1, from salicylic acid methyl ester and n-octylamine (quantities used 1 mole:1 mole) and purified and recrystallized in the same way as described in Example 1.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:25][N:26]([CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)=[CH:8]2)=[O:17]
Reactant: CNCCN1CCCCC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N(C)CCN4CCCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Methyl-(2-piperidin-1-yl-ethyl)-amine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid methyl-(2-piperidin-1-yl-ethyl)-amide. LC-MS: m/e 451 (MH+).
Reaction SMILES: [C:1]1(=[O:4])[CH2:3][CH2:2]1.[CH2:5]([O:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[SH:32])[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[S:32][C:1]2([OH:4])[CH2:3][CH2:2]2)[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OCc5ccccc5)CC[C@@]43C)[C@@H]1CC[C@@H]2S
Reactant: O=C1CC1
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OCc5ccccc5)CC[C@@]43C)[C@@H]1CC[C@@H]2SC1(O)CC1
Reaction time: 16 h

Procedure:
3β-Benzyloxyandrost-5-en-17β-thiol is obtained starting from dehydroepiandrosterone. The dehydroepiandrosterone is reacted with one equivalent of sodium hydride and benzyl chloride by standard procedures for making benzyl ethers to give 3-benzyloxyandrost-5-en-17-one. This benzyloxy compound is then reacted with Lawesson's reagent (4-methoxyphenylthiophosphine sulfide dimer) according to the procedure described in M. Feiser, "Feiser and Feiser's Reagents for Organic Synthesis", John Wiley & Sons, New York, 1980, p. 327; also B. S. Pedersen et al., Bull. Soc. Chim. Belg., 87, 223 (1978). This gives 3β-benzyloxyandrost-5-ene-17-thione and this thione is then reduced with lithium aluminum hydride by standard procedures to give the desired 17β-thiol. Then, to a solution of cyclopropanone in dichloromethane under nitrogen at -50° C., there is added rapidly 1.1 equivalent of the above thiol in dichloromethane. The temperature is allowed to rise to -30° C. and, after 16 hours, most of the solvent is evaporated. Dry ether is added to precipitate by-product polyketene. The by-product is removed by filtration, the solvent is distilled from the filtrate, and the residue is purified by flash chromatography to give 3β-benzyloxy-17β-(1-hydroxycyclopropylthio)androst-5-ene.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])[CH2:37][NH:36][C:35]2=[S:40])[N:29]=[CH:28]1.N1CCCCC1>ClCCl>[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])/[C:37](=[CH:17]/[C:15]3[O:16][C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=4)=[CH:13][CH:14]=3)/[NH:36][C:35]2=[S:40])[N:29]=[CH:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Reactant: O=C1CNC(=S)N1CCc1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\NC(=S)N(CCc4c[nH]cn4)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (65 mg, 0.14 mmol) synthesized by the same method as in Example 4 and 3-(2-(1H-imidazol-4-yl)ethyl)-2-thioxoimidazolidin-4-one (32 mg, 0.15 mmol) synthesized by the same method as in Example 3 were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol (9/1 (volume ratio)) as an eluent, to give labeling precursor 3 in a yield of 42 mg (yield 45.9%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C(Cl)/C=C/c1ccc(F)cc1
Yield: 105.3 %

Procedure:
A mixture of 15.0 g. (0.09 mole) of trans-4-fluorocinnamic acid (Compound LXXVI) and 30 ml. (0.41 mole) of thionyl chloride in 100 ml. of toluene is stirred at 70° C. for 18 hours, and the solvent is evaporated at reduced pressure to obtain the crude product (17.5 g. (>100%)).
Reaction SMILES: C(O)(=O)C.[CH2:5]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[BH4-].[Na+]>CS(C)=O>[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1ccc(/C=C/[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCCc1ccc(CC[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
To an acetic acid (5.7 mL) and dimethyl sulfoxide (95 mL) solution of 1-butyl-4-((E)-2-nitro-vinyl)-benzene (5.7 g, 27.8 mmol) described in Manufacturing Example 70-1-1 was added sodium borohydride (1.68 g, 44.5 mmol) at room temperature while cooling appropriately. This mixture was stirred for 3 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (1.48 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][CH3:35])[C:11](=[CH2:33])[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[CH:26][C:25](OC(F)(F)F)=[CH:24][CH:23]=3)[CH:17]=2)=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:47][C:48]([F:64])([F:63])C1C=CC(C2C=C(CN)C=CN=2)=CC=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][CH3:35])[C:11](=[CH2:33])[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:48]([F:64])([F:63])[F:47])=[CH:24][CH:23]=3)[CH:17]=2)=[O:13])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
Acid 7 (295.76 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv., 277.5 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (1:1 EtOAc:petroleum ether) afforded 100 mg of a beige solid. Yield=18.8% 1HNMR (DMSO, 200 MHz) δ 1.12 (3H, t, J=7 Hz), 3.47 (2H, q), 4.48 (2H, d, J=6.4 Hz), 5.41 (1H, s), 6.25 (1H, s), 7.34 (2H, m), 7.59 (1H, d, J=4 Hz), 7.84 (2H, d, J=8 Hz), 7.98 (1H, bs), 8.28 (2H, d, J=8 Hz), 8.63 (1H, d, J=5 Hz), 8.91 (1H, bt) [M+1] 530.1 (C22H19ClF3N3O3S2 requires 529.98).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].I[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:42][CH2:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=3)[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: CCCCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCCc4ccccc4)CC3)C2=O)c1
Yield: 91.4 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-iodo-4-butylbenzene (0.15 g, 0.593 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.30 g, 90%); MS for C35H43N3O3 m/z 554 (M+H)+.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>C(OCC)(=O)C>[CH3:46][C:42]1[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=1)[CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Cc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(Cc2cc(O)c(=O)[nH]n2)c1

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-methylphenyl)methyl]pyridazine (Intermediate 57) except that the solvent mixture used for the hydrogenation was made up from tetrahydrofuran and ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptane.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([Cl:31])=[N:29][CH:30]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:24][C:25]3[CH:26]=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([Cl:31])=[N:29][CH:30]=3)=[N:3][CH:4]=[C:5]([CH:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH3:17])[CH:6]=2)[N:9]=1
Reactant: Cc1nc(N)nc(-c2cc(C(C)N3CCOCC3)cnc2F)n1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoro-5-(1-morpholinoethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.314 mmol), N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (0.084 g, 0.377 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (0.254 mL, 1.256 mmol) was then added to the solution in one portion. The now brugundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stir for 1 h. The reaction mixture was extracted with EtOAc (2×10 mL), CHCl3 (2×10 mL). The combined organic layer were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (100 mg). MS (ESI pos. ion) m/z: 520.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34 (d, J=6.58 Hz, 3H) 2.33 (br. s., 2H) 2.46 (s, 5H) 3.13 (s, 3H) 3.46 (d, J=4.82 Hz, 1H) 3.57 (br. s., 4H) 7.69-8.00 (m, 2H) 8.32 (s, 1H) 8.66 (d, J=2.48 Hz, 2H) 8.74 (s, 1H) 9.65 (br. s., 1H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:2])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:23])([F:21])[F:22])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Yield: 96 %

Procedure:
As described for Example 48b, 6-{4-[3-(4-chloro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using 2,2,2-trifluoroethylamine instead of cyclopropanemethylamine, to the title compound (110 mg, 96%) which was obtained as a white solid. MS: m/e 516.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:9][O:10][CH2:11][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: Oc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromophenol (27.4 g, 158 mmol) in CH2Cl2 was added chloromethyl methyl ether (18 mL, 237 mmol). The reaction mixture was cooled to 0° C. and diisopropylethylamine (55 mL, 316 mmol) was added and the cold bath was removed. The reaction mixture was stirred for 3 hours at ambient temperature and then poured into 10% aqueous HCl. The layers were separated and the aqueous phase was extracted 4 times with CH2Cl2. The combined organic layers were washed once each with saturated aqueous NaHCO3, 15% aqueous NaOH, and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 3-methyloxymethoxy-bromobenzene as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:13]=[C:12]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:11]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]=[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:11]=2)[CH:6]=1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnn(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a cooled (0° C.) solution of 4-bromopyrazole (0.29 g, 2.0 mmol) in anhydrous DMF (4 ml) was added NaH (60% dispersion in mineral oil, 0.088 g, 2.2 mmol) in a portionwise fashion over 10 minutes. The mixture allowed to warm to room temperature where it was stirred for 30 minutes before the adition of 2-Chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (3b)(0.571 g, 2.00 mmol). The mixture was then heated under the influence of microwave radiation (120° C., 14 minutes). Upon cooling the reaction was diluted with water (10 ml) and filtered. The filtercake was washed with more cold water (10 ml), collected and dried to give the title compound (92.4%, 0.73 g) in suitably pure form to be used without any further purification. m/z (LC-MS, ESP): 396 [M+H]+, R/T=3.56 mins.