Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([C:21]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)([CH3:23])[CH3:22])[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([C:21]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)([CH3:23])[CH3:22])[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(C(C)(C)c4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(c1ccc2ncccc2c1)n1nnc2ccc(-c3ccc(C(=O)O)c(F)c3)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
To a solution of Example 82 (0.700 g, 1.60 mmol) in methanol (3.7 ml), lithium hydroxide (0.626 g, 14.94 mmol) in water (3.7 ml) and THF (14 ml) were added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.485 g, 71%) MS (m/z): 472.99 (M+).
Reaction SMILES: [Mo:1](=O)(=O)=[O:2].[O-2:5].[O-2].[O-2].[Bi:8]>O.[OH-].[NH4+].[N+]([O-])(O)=O>[O-2:2].[O-2:5].[O-2:2].[O-2:2].[O-2:2].[O-2:2].[O-2:2].[O-2:2].[O-2:2].[Mo:1].[Mo:1].[Bi+3:8].[Bi+3:8]
Reactant: O=[Mo](=O)=O
Reactant: [Bi]
Agent: [NH4+]
Agent: [O-2]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: [Bi+3]
Product: [Mo]
Temperature: 100 °C

Procedure:
171 grams of molybdenum trioxide (MoO3) were dissolved in a mixture of 433 ml of water and 215 ml of 57% ammonium hydroxide, added to a solution of 251.7 grams of bismuth trioxide (Bi2O3) in 833 ml of water and 367 ml of 70% nitric acid with stirring. The pH of the resulting mixtures were adjusted to between 1 and 6.5 using ammonium hydroxide and heated for approximately 2 hours at 100° C. The bismuth molybdate precipitate was filtered and washed with approximately 500 ml of water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14].N1CC[CH2:22][CH2:21]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:12]/[N:13]2[CH2:15][CH2:22][CH2:21][CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C1CCNC1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1/C=C/N1CCCC1
Yield: 108.7 %

Procedure:
To a stirred solution of 4-fluoro-2-nitrotoluene (50.0 g, 0.327 mol) in DMF (100 mL) was added DMF-DMA (52 mL, 0.392 mol) and pyrrolidine (33 ml, 0.392 mol) in DMF (100 mL). The reaction mixture was stirred at reflux overnight and then concentrated under reduced pressure, giving 84 g of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:23][CH:24](O)[CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=4[C:34]#[N:35])[CH2:28][CH2:27]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].CCN(S(F)(F)[F:47])CC.CO.C(Cl)Cl>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:23][CH:24]([F:47])[CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=4[C:34]#[N:35])[CH2:28][CH2:27]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(F)CN2CCN(c3ccccc3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A solution of 2-(4-{3-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (150 mg, 0.27 mmol) in CH2Cl2 (1 mL) was treated with DAST (Et2NSF3, 7 μL, 0.60 mmol) at −78° C. The reaction mixture was slowly warmed to 25° C. for 1 h and then to 60° C. for an additional 2 h. Preparative TLC (silica, 5% MeOH/CH2Cl2) provided 75 mg (50%) of the title compound as a light yellow powder. TLC (5% MeOH/CH2Cl2): Rf=0.28. MS (electrospray): m/z 555.2 ([M+H]+, C29H30F4N6O requires 554.2). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 7.71 and 7.59 (AB pattern, Jab=8.2 Hz, 2H), 7.66 and 7.62 (AB pattern, Jab=8.4 Hz, 2H), 7.50-7.38 (m, 2H), 6.96-6.92 (m, 2H), 5.01 (dp, J=49.0, 3.0 Hz, 1H), 4.77 and 4.73 (AB pattern, Jab=15.7 Hz, 1.1H), 4.59 (s, 0.9H), 4.41-4.18 (m, 2H), 3.95-3.80 (m, 1H), 3.69 (dd, J=5.5, 5.5 Hz, 1H), 3.18 (m, 4H), 2.83-2.65 (m, 8H), 2.14 (s, 1.6H), 2.10 (s, 1.4H).
Reaction SMILES: CO[C:3]([C:5]1([CH2:29][CH:30]=O)[CH2:10][CH2:9][CH:8]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6]1)=[O:4].[CH3:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH:38]1[CH2:42][CH2:41][C@H:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:11][CH:8]1[CH2:7][CH2:6][C:5]2([C:3](=[O:4])[N:49]([C:46]3[CH:47]=[CH:48][C:43]([CH:40]4[CH2:41][CH2:42][CH:38]([N:34]5[CH2:35][CH2:36][CH2:37][CH:33]5[CH3:32])[CH2:39]4)=[CH:44][CH:45]=3)[CH2:30][CH2:29]2)[CH2:10][CH2:9]1
Reactant: COC(=O)C1(CC=O)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: CC1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1CCCN1C1CCC(c2ccc(N3CCC4(CCC(O)CC4)C3=O)cc2)C1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 4-(tert-butyl-diphenyl-silanyloxy)-1-(2-oxo-ethyl)-cyclohexanecarboxylic acid methyl ester (Intermediate 8) with 4-[(S)-3-(2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 15), and subsequently cyclization, followed by de-protection with TBAF in THF at 60° C. for 5 h.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:23][CH:24]([CH:37]([CH3:39])[CH3:38])[CH:25]([O:30]C(=O)C(C)(C)C)[C:26]([F:29])([F:28])[F:27])=[O:22])[C:16]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)=C[CH:14]=2)=[O:11])[CH:5]=[C:4]([CH3:45])[N:3]=1.O.[OH-].[Li+].[Cl-].[NH4+:50]>O1CCCC1.CO.O>[CH3:45][C:4]1[CH:5]=[C:6]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:23][CH:24]([CH:37]([CH3:39])[CH3:38])[CH:25]([OH:30])[C:26]([F:28])([F:27])[F:29])=[O:22])[C:16]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)=[N:50][CH:14]=2)=[O:11])[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(COC(=O)Nc2ccc(-c3cccs3)n(CC(=O)NC(C(C)C)C(OC(=O)C(C)(C)C)C(F)(F)F)c2=O)cc(C)n1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(COC(=O)Nc2cnc(-c3cccs3)n(CC(=O)NC(C(C)C)C(O)C(F)(F)F)c2=O)cc(C)n1
Reaction time: 2 h

Procedure:
To a solution of 2-[5-(2,6-dimethylpyrid-4-ylmethoxycarbonylamino)-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyridinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-pivaloyloxypropyl)acetamide (1.44 g) in tetrahydrofuran (10 mL) and methanol (10 mL) was added a solution of lithium hydroxide monohydrate (0.92 g) in water (20 mL). The resulting solution was stirred for 2 h, diluted with saturated ammonium chloride (30 mL), and extracted with ethyl acetate. The ethyl acetate solution was dried and evaporated. The resulting material was chromatographed, eluting with ethyl acetate, to provide the alcohol (0.39 g) as a yellow foam; TLC: Rf =0.24, ethyl acetate; MS: m/z=568(M+1).
Reaction SMILES: C(Cl)Cl.[NH:4](C(OC(C)(C)C)=O)[C@H:5]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:6][CH2:7][C:8](=[O:10])O.Cl.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:38][C:39]1[CH:40]=[C:41]([Cl:50])[C:42]([CH3:49])=[C:43]([S:45]([OH:48])(=[O:47])=[O:46])[CH:44]=1>FC(F)(F)C(O)=O.C1COCC1>[Cl:50][C:41]1[CH:40]=[C:39]([NH:38][C:8](=[O:10])[CH2:7][CH2:6][C@@H:5]([C:11]([OH:13])=[O:12])[NH2:4])[CH:44]=[C:43]([S:45]([OH:48])(=[O:47])=[O:46])[C:42]=1[CH3:49]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1c(Cl)cc(N)cc1S(=O)(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)cc(NC(=O)CC[C@H](N)C(=O)O)cc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After 1 ml of methylene chloride and 1 ml of THF were added to 303 mg (1 mmol) of Boc-Glu-OtBu hydrochloride and 180 mg (1.1 mmol) of CDI, 221 mg of 5-amino-3-chloro-2-methylbenzenesulfonic acid was further added to mixture. The mixture was stirred at room temperature overnight and then purified in accordance with the purification step A to give the protected form of the intended product. The obtained protected product was dissolved in 5 ml of trifluoroacetic acid. The solution was stirred for 2 hours. The solvent was distilled off and the mixture was purified in accordance with the purification step A to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](C(C2C(O)=CC3C(C)(C)CCC(C)(C)C=3C=2)=O)=[CH:6][CH:5]=1.[H-].[Na+].BrCCCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCBr
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 171.2 %

Procedure:
A solution of the 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (433 mg, 1.18 mmol) in DMF (2 mL) was treated with NaH (1.5 mmol) at 0° C. and allowed to warm to ambient temperature over 1 h. The yellow solution was cooled again to 0° C., and treated with a solution of bromobutane (119 mL, 1.30 mmol) in DMF (1 mL) and allowed to warm to ambient temperature and stirred for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated to give a colorless oil. Purification by silica gel flash chromatography (20:1=hexanes:Et2O) gave 4-[3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester 275 mg (55%) as a white solid: 1H NMR (400 MHz, CDCl3) δ8.07 (½ABq, J=8.2 Hz, 2H, ArH), 7.81 (½ABq, J=8.2 Hz, 2H, ArH), 7.44 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.95 (s, 3H, OCH3), 3.81 (t, J=6.2 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.34 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.27 (s, 6H, 2CH3), 1.02 (m, 2H, CH2), 0.71 (t, J=7.2 Hz, 3H, CH3); HRMS calcd. for C27H34O4 423.2535 (MH+), found 423.2505. The butyloxy keto ester (150 mg, 0.36 mmol) was hydrolyzed with excess KOH in MeOH as described in Example 1 to give 4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid (111) 82 mg (59%) as a white solid: mp 207-210° C.; 1H NMR (400 MHz, CDCl3) δ8.14 (½ABq, J=8.2 Hz, 2H, ArH), 7.84 (½ABq, J=8.2 Hz, 2H, ArH), 7.46 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.81 (t, J=6.2 Hz, 2H, OCH2), 1.71 (m, 4H, 2CH2), 1.32 (s, 6H, 2CH3), 1.29 (m, 2H, CH2), 1.28 (s, 6H, 2CH3), 1.00 (m, 2H, CH2), 0.72 (t, J=7.3 Hz, 3H, CH3); HRMS calcd. for C26H32O4 408.2301 (M+), found 408.2300.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](OCC)(=O)[CH2:22][C:23]([NH2:25])=[O:24].[H-].[Na+]>>[OH:24][C:23]1[C:22]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][C:12]2[CH2:13][CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][C:11]=2[N:25]=1
Reactant: CCOC(=O)CC(N)=O
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2c(nc1O)CCN(Cc1ccccc1)CC2

Procedure:
Prepared from 1-benzyl-hexahydro-4-azepinone with ethyl formate and ethyl malonamate in the presence of sodium hydride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[C:13]1([CH2:12][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)cc1

Procedure:
To a solution of 36.6 g (0.3 mol) of 4-hydroxybenzaldehyde in 100 ml of ethanol were added dropwise, one after another, a solution of 12.0 g (0.3 mol) of sodium hydroxide in 100 ml of water and a solution of 36.5 ml of (0.307 mol) of benzylbromide in 100 ml of ethanol and the mixture was then kept for 1 hour at 50° C. The ethanol was extensively distilled off, finally in vacuo, the remaining aqueous emulsion was divided between water and ethyl acetate. The ethyl acetate phase was dried over sodium sulphate and evaporated down in vacuo. The residue remaining crystallised on trituration with petroleum ether and was recrystallised from diisopropylether. 48.0 g (75.4% of theory) of colourless crystals of melting point 118-122° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Te:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([Te:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:28][CH:27]=1.[CH:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH:3]=[CH:4][C:5]2=[O:12])=[O:1])=[CH:10][CH:9]=1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Reactant: Oc1ccc(O)c2ccccc12
Solvent: ClC(Cl)Cl
Product: COc1ccc([Te]c2ccc(OC)cc2)cc1
Product: O=C1C=CC(=O)c2ccccc21
Yield: 97 %
Yield: 56 %

Procedure:
1,4-Dihydroxynaphthalene (80 mg, 0.50 mmol) and bis-(p-methoxyphenyl)-telluroxide (196 mg, 0.55 mmol) were stirred in chloroform (4 ml) at room temperature under argon for 1 h. The reaction mixture was concentrated by evaporation of the solvent under reduced pressure and p.l.c. (benzene-ethyl acetate 9:1) gave bis-(p-methoxyphenyl)-telluride (96 mg, 56%) and p-naphthoquinone (77 mg, 97%) as an olive green solid m.p. 122°-125° which on recrystallisation from ethanol gave yellow needles (60 mg, 76%) m.p. 125°-126° (lit., 126) δ(CDCl3) 8.27-7.67 (4H, m), and 7.00 (2H, S).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH2:60][CH2:61][C:62]([O:64][CH3:65])=[O:63]>CN(C)C=O>[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH2:60][CH2:61][C:62]([O:64][CH3:65])=[O:63])[C:11]([C:7]1[N:6]=[C:5]2[N:4]=[C:3]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)[N:2]([CH3:1])[C:10]2=[CH:9][CH:8]=1)=[O:12]
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(C(=O)O)ccc21
Reactant: COC(=O)CCNc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CCN(C(=O)c1ccc2c(n1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
308 mg (1.0 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-carboxyimidazo[4,5-b]pyridine were suspended in 5 mL of dimethylformamide and mixed with 303 mg (3.0 mmol) of N-methylmorpholine and 321 mg (1.0 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate. After 10 minutes at room temperature, a solution of 215 mg (1.2 mmol) of methyl N-(2-pyridyl)-3-aminopropionate in 2 mL of dimethylformamide was added, whereupon a clear solution was obtained. After 12 hours at room temperature, the reaction solution was stirred into ice-water. After extracting 3 times with ethyl acetate, the combined organic extracts were washed with a saline solution, dried over sodium sulfate, and evaporated down. The residue obtained was chromatographed on silica gel with dichloromethane/ethanol (90:1 to 25:1). Yield: 165 mg of white powder (35% of theory), C25H12N6O4 (407.50); melting point: 139° C.-140° C.
Reaction SMILES: [N+](C1C=CC(C=[N:9][NH:10][C:11]2[N:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=CC=1)([O-])=O.C1C=CC=CC=1.C1(C)C=CC=CC=1.[Cl:38]CCl>C(Cl)(Cl)Cl>[ClH:38].[ClH:38].[O:20]1[CH2:21][CH2:22][N:17]([C:14]2[N:13]=[N:12][C:11]([NH:10][NH2:9])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1
Reactant: ClCCl
Reactant: O=[N+]([O-])c1ccc(C=NNc2ccc(N3CCOCC3)nn2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Cl
Product: NNc1ccc(N2CCOCC2)nn1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
One part by weight of the substituted benzylidenehydrazine (compounds of Examples 1 to 6) is heated together with 20 parts by volume of benzene (or toluene or dichloromethane or chloroform) and 20 parts by volume of concentrated hydrochloric (or 48% hydrobromic) acid while stirring at an internal temperature of 40° C. for 1 to 2 hours in such a way that the organic phase is replaced by fresh solvent every 30 minutes. After separation 80-90% of the substituted benzaldehyde can be recovered from the organic phase. From the acidic aqueous phase, 6-morpholino-3-pyridazinylhydrazine dihydrochloride (or dihydrobromide, respectively) is obtained after evaporation and triturating the residue with ethanol and ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:26]1([CH3:29])[CH2:28][CH2:27]1.Cl>CC(C)=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:7]([CH2:29][CH:26]2[CH2:28][CH2:27]2)[C:6]1=[O:17]
Reactant: COC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: CC1(Br)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC2CC2)c1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
300 mg (1.13 mmol) of the compound from Example 232A together with 1.10 g (3.38 mmol) of caesium carbonate are placed in 12 ml acetone and treated with 456 mg (3.38 mmol) of bromo-methylcyclopropane. This is stirred for 2 hrs at 50° C. The reaction mixture is then diluted with 10 ml each of ethyl acetate and water and acidified with 1 N hydrochloric acid. The phases are separated and the aqueous phase is once again extracted with 10 ml ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. Further purification is effected by preparative HPLC [Method 10]. 60 mg (17% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1.N12CCCN=C1CCCCC2.[I-].[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(#N)C>[CH2:3]([C:4]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=2)=[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]2[N:27]=1)[CH:2]([CH3:14])[CH3:1]
Reactant: CSc1nccc(C#CCC(C)C)n1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CSc1nccc(-c2c(CC(C)C)nn3ccccc23)n1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a cold (0° C.) solution of 4-(4-methylpent-1-ynyl)-2-(methylthio)pyrimidine (2.5 g, 12 mmol) in acetonitrile (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.7 mL, 18 mmol) and 1-aminopyridinium iodide (3.49 g, 15.7 mmol). The resultant dark solution was allowed to warm to room temperature and stirred vigorously. The mixture was heated to 50° C. for 18 h then cooled to room temperature. Water was added and the mixture concentrated in vacuo. The residue was partitioned between water and ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (6:1 to 4:1 to 2:1 hexane-ethyl acetate) provided 2-isobutyl-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (2.0 g, 56%) as a yellow solid. 1H NMR (CDCl3) δ 8.51–8.48 (m, 2H), 8.36 (d, 1H), 7.35 (t, 1H), 7.19 (d, 1H), 6.91 (t, 1H), 3.04 (d, 2H), 2.68 (s, 3H), 2.20 (m, 1H), 1.03 (d, 6H); MS m/z 299 (M+1).
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][CH2:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.S(=O)(=O)(O)[OH:22]>O>[CH3:18][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:7][C:6](=[O:22])[CH:5]=[CH2:4]
Reactant: CCN(CC)CC#CCC(C)Cc1cccc(OC)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: C=CC(=O)CC(C)Cc1cccc(OC)c1

Procedure:
Add mercuric sulphate (0.45 g) to a stirred solution of 1-diethylamino-5-methyl-6-(m-methoxyphenyl)hex-2-yne (8 g) in concentrated sulfuric acid (2.5 cc) and water (25 cc) and heat the mixture at 70° for 11/2 hours. Filter the coled solution, make basic with 10% aqueous sodium hydroxide and extract with ether. Wash and dry the ethereal solution and evaporate to leave as residue crude 1-diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-one; infrared absorption peaks at 5.85 μ. Slowly distil at 0.1 mm Hg to obtain 5-methyl-6-(m-methoxyphenyl)hex-1-en-3-one; infrared absorption peaks at 5.82 μ.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([O:22][CH3:23])[C:17]=1[C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([C:17]3[C:18]([O:22][CH3:23])=[N:19][N:20]([CH3:21])[C:16]=3[NH:15][S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.5 %

Procedure:
To a solution of 4-dimethylaminopyridine in anhydrous pyridine at 0° C. under an atmosphere of nitrogen was added 4-(trifluoromethyl)benzenesulfonyl chloride (148 mg) in pyridine (1.5 ml). After 10 min the reaction was treated with 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and the reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was concentrated under reduced pressure, the residue treated with 1.0M aqueous citric acid (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (eluent of 55% water in acetonitrile to 30% water in acetonitrile over 8 mins, then 30% water in acetonitrile for 13 mins. Phenomenex Magellen™ 150 mm×21.5 mm column, 40° C.) to yield the title compound as an off-white solid (1 mg).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])([CH3:4])[CH3:3].[CH3:13][N:14]=[C:15]=[O:16]>C(Cl)(Cl)Cl>[CH3:4][C:2]([N:5]([CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:15]([NH:14][CH3:13])=[O:16])([CH3:1])[CH3:3].[CH3:4][C:2]([N:5]([CH2:6][CH:7]([O:12][C:15](=[O:16])[NH:14][CH3:13])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:15]([NH:14][CH3:13])=[O:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)N(CC(O)C(Cl)(Cl)Cl)C(C)(C)C
Product: CNC(=O)OC(CN(C(=O)NC)C(C)(C)C)C(Cl)(Cl)Cl

Procedure:
The reaction of 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol with methyl isocyanate normally takes place at -70° to +80° C. in an inert solvent such as chloroform to produce 1-(1,1-dimethylethyl)-3-methyl-1-(3,3,3-trichloro-2-hydroxypropyl)urea and 1-(1,1-dimethylethyl)-3-methyl-1-[3,3,3-trichloro-2-(methylcarbamoyloxy)propyl]urea.