Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[N+:2]=[N-:3].[CH:13](OC)=[O:14]>>[CH:13]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH2:12][CH2:11]1)=[O:14]
Reactant: COC=O
Reactant: [N-]=[N+]=NCCCC1CCNCC1
Product: [N-]=[N+]=NCCCC1CCN(C=O)CC1

Procedure:
A solution of 4-(3'-azidopropyl)-piperidine (1.5 g) in methyl formate (5 ml) was refluxed for 1 hour. Evaporation to dryness gave the desired compound as an oil. The IR-spectrum (CHCl3) showed strong bands at 2100, 1660, 1440 and 1270 cm-1.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)Br.O=C[C@H](NC(=O)OC(C)(C)C)C.Br[C:38](Br)=[CH:39][C@H:40]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH3:41].[Li]CCCC>C(Cl)Cl.C1COCC1.[Zn]>[CH3:41][C@@H:40]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]#[CH:38]
Reactant: C[C@H](C=C(Br)Br)NC(=O)OC(C)(C)C
Agent: BrC(Br)(Br)Br
Agent: C[C@H](C=O)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#C[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of zinc (135 g, 2.08 mol), PPh3 (545 g, 2.08 mol) and CBr4 (682 g, 4.08 mol) in CH2Cl2 (2 L) was stirred at 0° C. for 1.5 hr. A solution of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (114 g, 0.66 mol) in DCM was added in one portion, and the reaction mixture was stirred at 0° C. for another 3 hr. The mixture was quickly passed though a silica gel, and the solvent was evaporated to give the crude (R)-tert-butyl 4,4-dibromobut-3-en-2-ylcarbamate. To a cooled (−78° C.) solution of the crude compound (R)-tert-butyl 4,4-dibromobut-3-en-2-ylcarbamate in THF (2 L) was added dropwise 2.5 M BuLi (0.75 L, 1.88 mol) under nitrogen. The reaction was quenched with water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over MgSO4, filtered and concentrated to give the crude compound N.2, (R)-tert-butyl but-3-yn-2-ylcarbamate, which was used without further purification. 1H NMR (CDCl3) δ4.47 (br s, 1H), 2.24 (s, 1H), 1.49 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH2:16][C:17]#[N:18])[CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[N:21]=2)=[CH:4][CH:3]=1.C(O)C.[H][H]>O=[Pt]=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][NH2:18])[CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[N:21]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3cc(CC#N)ccn23)n1
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3cc(CCN)ccn23)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 300 mL pressure bottle containing nitrile 22 (980 mg, 2.41 mmol) was charged with ethanol (18 mL), chloroform (2 mL), and then PtO2 (200 mg, 0.881 mmol). The pressure bottle was then sealed, then charged with 50 psi hydrogen, and the reaction mixture was allowed to stir at room temperature for 12 hours, after which additional PtO2 (500 mg, 1.14 mmol) was added, and an the pressure bottle was charged with an additional 50 psi hydrogen then sealed, and the reaction mixture was stirred at room temperature for 3 hours. At this point, TLC analysis showed the reaction to be complete. The reaction mixture was then filtered through successive 0.45 □m Gelman nylon acrodiscs. The filtrate was then concentrated under reduced pressure and carried onto the next step without further purification. Crude yield of 23: 1.20 g (121%). MS (ESI+) 412.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:12]([CH2:41][OH:42])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C([C@@H](NC(N2CCOCC2)=O)CC2C3C(=CC=CC=3)C=CC=2)=O)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:47].[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:57]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:54](O)=[O:55])=[O:51]>>[CH3:48][O:49][C:50](=[O:51])[NH:52][C@H:53]([C:54](=[O:55])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Cl:47])[CH:4]=1)(=[O:10])=[O:9])[CH2:43][CH:44]([CH3:45])[CH3:46])[CH2:41][OH:42])[CH:57]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)c(Cl)c1
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)c(Cl)c1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from (1S)4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-3-chloro-N-isobutyl-benzenesulfonamide (XII) (example 44, step B) as described in general procedure B using (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (see example 34, step A). The final product was obtained in 43% yield (48 mg).
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:16](C#N)=[CH:15][C:14]=1[Cl:22])=[N+:2]=[N-:3].N(C1C(Cl)=CN=CC=1C=O)=[N+]=[N-].ClC1C=CC=C(Cl)C=1N>>[N:1]([C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][CH:16]=[CH:15][C:14]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: N#Cc1cc(Cl)c(/N=C/c2cncc(Cl)c2N=[N+]=[N-])c(Cl)c1
Agent: Nc1c(Cl)cccc1Cl
Agent: [N-]=[N+]=Nc1c(Cl)cncc1C=O
Product: [N-]=[N+]=Nc1c(Cl)cncc1/C=N/c1c(Cl)cccc1Cl

Procedure:
Following the procedure described for 4-{[1-(4-azido-5-chloropyridin-3-yl)meth-(E)-ylidene]amino}-3,5-dichlorobenzonitrile, 4-azido-5-chloropyridine-3-carbaldehyde and 2,6-dichloroaniline were reacted to afford the title compound as a beige solid that was used without purification.
Reaction SMILES: C([NH:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@@H:19]3[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:29])([OH:28])[OH:27])[C@@H:21]([OH:30])[C@H:20]3[OH:31])[N:17]=[CH:18][C:11]=12)(=O)C1C=CC=CC=1.[NH4+].[OH-]>>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@@H:19]3[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:27])([OH:28])[OH:29])[C@@H:21]([OH:30])[C@H:20]3[OH:31])[N:17]=[CH:18][C:11]=12
Reactant: O=C(Nc1ncnc2c1cnn2[C@@H]1O[C@H](/C=C/P(=O)(O)O)[C@@H](O)[C@H]1O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2c1cnn2[C@@H]1O[C@H](/C=C/P(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.7 %

Procedure:
Compound 25.2 (19.3 mg, 0.431 mmol) was treated with concentrated NH4OH (2.2 mL, 0.02 M) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was treated with 1% AcOH (2 mL). Reverse phase HPLC afforded compound 25.3 (7.0 mg, 47% yield) as a white solid: 1H NMR (D2O, 300 MHz) 8.10 (s, 2H), 6.26 (m, 1H), 6.19 (m, 1H), 5.85 (m, 1H), 4.77 (m, 1H), 4.51 (m, 1H), 4.31 (m, 1H); 31P NMR (D2O, 121.4 MHz) 9.6; MS (ESI) m/z 344 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH:25]([CH3:27])[CH3:26])[CH2:11][CH:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13](OC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[CH2:1]([O:8][CH2:9][CH:10]([CH:25]([CH3:27])[CH3:26])[CH2:11][CH:12]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CC(COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(COCc1ccccc1)CC(CO)NC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of 20.0 g of methyl 4-benzyloxymethyl-2-tert-butoxycarbonylamino-5-methylhexanoate [180182-92-7] in 320 ml of tetrahydrofuran at room temperature is admixed with 2.64 g of lithium borohydride in portions. After 4 hours, the reaction mixture is quenched with 200 ml of methanol dropwise over 1 hour and subsequently concentrated cautiously by evaporation. The residue is admixed once again with 150 ml of methanol and again concentrated by evaporation to dryness. The residue is admixed with 100 g of ice and 400 ml of 1N HCl and extracted with dichloromethane (3×)—the combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as an beige oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.32 (1:1 EtOAc-heptane). Rt=4.96 (gradient I).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.[F:13][C:14]([F:34])([F:33])[C:15]1[CH:32]=[CH:31][CH:30]=[CH:29][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=[O:18]>O1CCCC1.CCCCCC>[OH:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])([C:16]1[CH:29]=[CH:30][CH:31]=[CH:32][C:15]=1[C:14]([F:33])([F:34])[F:13])[CH2:2][C:1]#[N:4]
Reactant: O=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(O)(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of diisopropylamine (4.02 mL) in dry tetrahydrofurane (30 mL) under argon was treated dropwise with 1.6M n-butyl lithium in hexane (18 mL). The reaction was kept at -5° C. during the addition and for 15 minutes thereafter, then it was cooled to -78° C. and a solution of 2,2'-bis(trifluoromethyl)benzophenone (8.0 g) in tetrahydrofurane was added at such a rate that the reaction temperature did not exceed -65° C. The mixture was stirred at -78° C. for 10 minutes, then it was allowed to slowly equilibrate to room temperature over 30 minutes. After the solvents were removed under reduced pressure, the residue was treated with water (100 mL) and the resulting solid was filtered off, washed with water and dried. Crystallization of the solid from dichloromethanehexane furnished 7.72 g of 3-hydroxy-3,3-bis[2-(trifluoromethyl)phenyl]-propanenitrile, mp 168°-170° C. A sample was recrystallized from the same solvent system to give the analytical specimen, mp 171°-172° C. Anal. Calculated for C17H11F6NO: 56.83: H, 3.08: F, 31.73: N, 3.80. Found: C. 56.87; H, 2.81: F, 31.88: N, 4.14.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH2:12]1)=[O:10].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:42])[C:36]=3[NH:35][C:34]3[CH:43]=[CH:44][CH:45]=[CH:46][C:33]2=3)=[O:31])=[CH:26][CH:25]=1>C(#N)C>[CH3:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:41][C:40]4[CH:39]=[N:38][N:37]([CH3:42])[C:36]=4[NH:35][C:34]4[CH:43]=[CH:44][CH:45]=[CH:46][C:33]3=4)=[O:31])=[CH:26][CH:25]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)CCN1CCN(C(=O)CBr)CC1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(O)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCC(=O)N3CCN(CCC(C)(C)C)CC3)cc1)C2
Yield: 11 %

Procedure:
Potassium carbonate (104 mg, 0.76 mmol) was added to a mixture of 2-bromo-1-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-ethanone from Example E37 (110 mg, 0.38 mmol) and (4-hydroxy-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone from Example E75.2 (90 mg, 0.28 mmol) in acetonitrile (5 ml). The mixture was heated at reflux for 20 h then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with 5% KHCO3 solution, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white powder identified as the title compound (21 mg, 11%).
Reaction SMILES: [K].[O:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:4][C:3]1=[S:12].[CH2:13](I)[CH2:14][CH3:15]>[Hg]>[CH2:13]([S:12][C:3]1[O:2][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][N:4]=1)[CH2:14][CH3:15]
Reactant: CCOC(=O)c1n[nH]c(=S)o1
Reactant: CCCI
Agent: [Hg]
Agent: [K]
Product: CCCSc1nnc(C(=O)OCC)o1

Procedure:
The title compound was prepared from ethyl 1,3,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate (10 g., 28.5 mmole) and n-propyliodide (4.17 ml., 42.8 mmole) analogously to the procedure described in Experiment A. The yield was 4.99 g. (81%). The product had a B.P. of 108°-118° C. at 0.65 mm. of mercury.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([F:36])([F:35])[F:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4C(F)(F)F)c3O2)cc1
Yield: 93 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.01 g, 10.0 mmol) with 2-(trifluoromethyl)-phenyl boronic acid (2.85 g, 15.0 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.786 g, 1.00 mmol), and potassium carbonate (3.46 g, 25.00 mmol) generally according to the procedure described for Intermediate 37 provided 4.34 g (93%) of (±)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. Rf=0.54 (silica, ethyl acetate:hexanes 3:7); Anal. calcd. for C23H18F4O4S: C, 59.22; H, 3.89. Found: C, 60.19; H, 4.29.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][OH:18])[S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: OCCNCCO
Product: O=S(=O)(c1cncc(Br)c1)N(CCO)CCO
Yield: 41.5 %

Procedure:
Prepared by general procedure III from 5-bromo-pyridine-3-sulfonyl chloride (Example B.2 step 2) (500 mg, 2 mmol) and diethanolamine (1.03 g, 10 mmol) to give the title compound as an off-white solid (270 mg, 42%). MS (ISP) 325.1 [(M+H)+], 327.1 [(M+2+H)+].
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].Br[CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C(=O)(O)[O-].[Na+]>O>[CH2:1]([NH:4][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C#CCNC(C)C(=O)OC
Temperature: 80 °C
Yield: 37.7 %

Procedure:
Into a 250 ml round bottom flask are placed 26 g (0.47 mole) of propargylamine, 78.8 g (0.47 mole) of methyl 2-bromopropionate, and 39.7 g (0.47 mole) of sodium bicarbonate. The reaction mixture is heated at 80° C. overnight. It is cooled and poured into 200 ml of water. Extraction with ether provides 45 g of crude product which is further purified by vacuum distillation (94°-95°/3 mm) to give 25 g of desired product.
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].[C:13](OC(=O)C)(=[O:15])[CH3:14]>ClCCl>[CH3:4][C:2]([N:5]([CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:13](=[O:15])[CH3:14])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N(CC(O)C(Cl)(Cl)Cl)C(C)(C)C

Procedure:
The reaction of 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol with acetic anhydride takes place at about -70° to +70° C. in a solvent such as dichloromethane to produce the N-(1,1-dimethylethyl)-N-(3,3,3-trichloro-2-hydroxypropyl)acetamide of this invention.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:36].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:7]([C:16]([NH2:17])=[O:36])=[C:8]([CH:10]([OH:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Following a procedure similar to that described in Example 74(d), but using 0.34 g of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in a 1N aqueous solution of sodium hydroxide. 0.30 g of the title compound was obtained as a powder, melting at 157°-160° C.
Reaction SMILES: [Na].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:26][CH2:27][CH2:28][O:29][C:30]4[N:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=4)=[N:13][N:14]([CH3:25])[C:15]=3[N:16](S(C)(=O)=O)[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1>CO.ClCCl.[Cl-].[NH4+]>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:26][CH2:27][CH2:28][O:29][C:30]4[N:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=4)=[N:13][N:14]([CH3:25])[C:15]=3[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N(S(C)(=O)=O)S(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1NS(C)(=O)=O
Yield: 77 %

Procedure:
An aqueous solution of sodium hydroxyde (1M, 0.91 ml) was added at room temperature to a solution of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-N-(methylsulfonyl)methane sulfonamide (Preparation 49) (50 mg) in a mixture of methanol (1 ml) and dichloromethane (0.3 ml). After 1 h the reaction was diluted with an aqueous saturated solution of ammonium chloride (4 ml) and the mixture was extracted with dichloromethane (3*5 ml). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The pale yellow oil was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) to yield the title compound as a colourless oil (33 mg)
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11]([O:13]CC)=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C(=O)O)cc(C)c1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of ethyl 5-cyano-6-methoxy-4-methylpicolinate (1.0 g, 4.54 mmol) in MeOH (30 mL) and THF (10 mL) was added 6N NaOH (2 mL, 12.00 mmol). The suspension was heated to 60° C. and stirred for 2 hr. (The reaction cleared up right away.) LCMS indicated that the reaction was complete. The reaction was cooled to RT and concentrated to near dryness. The slurry was neutralized with 6N HCl (2 mL) diluted with water, filtered, washed with water and dried under vacuum to give the product 5-cyano-6-methoxy-4-methylpicolinic acid (0.76 g, 3.95 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.65 (br. s., 1H), 7.73 (s, 1H), 4.03 (s, 3H), 2.54 (s, 3H). MS (ES)+m/e 192.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl:17]N1C(=O)CCC1=O>CCCCCC.C1COCC1.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([Cl:17])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: Clc1nc(N2CCOCC2)c2sc(Cl)cc2n1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
n-Butylithium (1.6 mL, 3.914 mmol) in 2.5 M hexane solution was added to a mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (500 mg, 1.957 mmol) in 10 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 40 min. A solution of N-chlorosuccinimide (523 mg, 3.914 mmol) in 8 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The reaction was monitored by LC/MS. The mixture was diluted with ether and extracted with 1N HCl (2×60 mL). The aqueous layer was then basified and extracted with ethyl acetate (2×100 mL). The organic layer was washed with H2O (60 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by ISCO Combiflash (5-50% ethyl acetate/hexane) to afford 2,6-dichloro-4-morpholinothieno[3,2-d]pyrimidine (284 mg, 50%).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[Cl:29])[N:20]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[Cl:29])[N:20]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2c(Cl)cccc2n1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2c(Cl)cccc2n1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.5 %

Procedure:
Pyridine (1 ml) and 4-chlorobenzenesulfonyl chloride (255 mg) were added to 2-amino-5-chloroquinoline (119 mg, Preparation Example 2) at room temperature. After stirring at room temperature for 3 days, water was added thereto and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated. Then, the resulting solid was washed with methanol, to give the title compound (20 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.O>C(OCC)(=O)C>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: c1cc(C2CC2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-Boc-4-(4-bromophenoxy)piperidine (5 g) in toluene (70 mL) were added dichlorobis(tricyclohexylphosphine)palladium (II) (725 mg), tripotassium phosphate (14.9 g) and cyclopropylboronic acid (1.81 g), and the mixture was refluxed for 7 hr. After cooling, water was added, insoluble materials were filtered off, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated and the residue was purified by column chromatography to give 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester. 4-(4-Cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester was dissolve in ethyl acetate (3 mL), 4N hydrogen chloride/ethyl acetate (7 mL) was added, and the mixture was stirred at room temperature overnight. Water was added, and the mixture was washed with ethyl acetate. To the aqueous solution was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(4-cyclopropylphenoxy)piperidine (2.49 g). By reaction and treatment in the same manner as in Preparation Example 60 and using 6-bromonicotinic acid (1.2 g) and 4-(4-cyclopropylphenoxy)piperidine (1.4 g), the title compound (2.4 g) was obtained.