Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=C1C=CC2C(=CC=CC=2S([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]=[N+:24]=[N-:25])=[CH:19][CH:18]=2)(=O)=O)C1=O)=[N-].[N+:27](=[C:29]1[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:43])=[N-:28]>>[N+:27](=[C:29]1[CH:38]=[C:37]([S:39]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]=[N+:24]=[N-:25])=[CH:19][CH:18]=2)(=[O:41])=[O:40])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:43])=[N-:28]
Reactant: [N-]=[N+]=C1C=C(S(=O)(=O)Cl)c2ccccc2C1=O
Reactant: [N-]=[N+]=Nc1ccc(OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)cc1
Product: [N-]=[N+]=Nc1ccc(OS(=O)(=O)C2=CC(=[N+]=[N-])C(=O)c3ccccc32)cc1

Procedure:
This compound is prepared in a similar manner to Compound 1 but 2-diazo-1,2-dihydro-1-oxonaphthalene-4-sulfonyl chloride (2.2 grams) is used instead of the corresponding 5-sulfonyl chloride. The product is crystallized from ethanol. Yield of Compound 7 as a pure product is 1.1 gram, m.p. 131°-132°C (with decomposition).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:19][N:12]([C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CNCCN1
Reactant: CN(c1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: CN(c1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-(N-methylanilino)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 150°-152° C.) and piperazine.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([OH:32])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:36][C@H:37]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=[O:35])C>>[C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([O:32][C:33]([O:36][CH3:37])=[O:35])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][CH2:20][O:21]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2OC12
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCCO4)CC[C@H]3[C@H]12
Yield: 74.9 %

Procedure:
The procedure of Example 12 was repeated except that 44.6 mg (0.1 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2 -epoxy-7α-hydroxypregn-5-en-3β-yl acetate was used in lieu of 49.0 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregn-5-en-3β-yl acetate to give 37.8 mg of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate (yield: 75%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O)[C:5]([CH:7]1[CH2:9][CH2:8]1)=O.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:30])[F:29])[CH:22]=2)[C:5]=1[CH:7]1[CH2:9][CH2:8]1)=[O:18]
Reactant: COC(=O)C(C(=O)c1cccnc1)C(=O)C1CC1
Reactant: NNc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2cccnc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Yield: 8.5 %

Procedure:
A solution of gave 3-cyclopropyl-3-oxo-2-(pyridine-3-carbonyl)-propionic acid methyl ester (326 mg, 1.25 mmol) and 3-(trifluoromethyl)phenylhydrazine (220 mg, 1.12 mmol) in 2 ml acetic acid was stirred 20 h at room temperature. The reaction mixture was evaporated, the residue treated with EtOAc:n-heptane 1:1 and filtered off. The filtrate was concentrated in vacuo and chromatographed (amino-phase silica gel, EtOAc:n-heptane 1:1) to yield the title compound as a light yellow gum (37 mg, 8%). MS: 388.3 (MH+).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][C:24]([F:23])([F:34])[F:35])=[CH:27][CH:28]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (60 mg, 0.185 mmol, prepared as described in Example 55, Part B) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. 4-(Trifluoromethoxy)benzaldehyde (45.7 mg, 0.240 mmol, 1.3 equivalents) was added followed by triethylamine (0.051 mL, 0.369 mmol, 2.0 equiv). After stirring for 10 minutes, sodium triacetoxyborohydride (94 mg, 0.443 mmol, 2.4 equivalents) was added, and the reaction was stirred at room temperature for an additional four hours. The suspension was loaded directly onto a 4 g silica gel column and eluted with ethyl acetate (flow rate=18 mL/minute) over 20 minutes to give the title compound as a light yellow oil (42 mg, 50%). 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (d, J=1.2 Hz, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.44-5.24 (m, 1H), 4.10 (td, J=9.3, 4.5 Hz, 1H), 3.88 (dd, J=13.2, 5.2 Hz, 1H), 3.74 (dd, J=13.2, 2.0 Hz, 1H), 3.59 (s, 2H), 2.91 (dd, J=12.6, 6.8 Hz, 1H), 2.86-2.71 (m, 2H), 2.71-2.50 (m, 2H), 2.50-2.31 (m, 2H), 2.08-1.82 (m, 2H), 1.00-0.88 (m, 4H); MS (ESI+) m/z 463.1 (M+H)+; [a]D23.6=0.08 (c=0.17, CH3OH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[I:22]Cl.II>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([I:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
Reactant: ClI
Agent: II
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2c1COC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester in 20 ml of methylene chloride and 1.5 ml of pyridine is mixed dropwise with 1.5 ml of iodine chloride at room temperature. After 60 minutes, another 1.5 ml of iodine chloride is added and then 200 mg of iodine. The mixture is stirred for another 2 h at room temperature and then poured into an ice-cold saturated sodium thiosulfate solution, followed by extraction with methylene chloride. Crystallization in ethyl acetate yields 520 mg of 6-iodo-4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 204°-206° C.
Reaction SMILES: [OH-:1].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[CH:6]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[F:12][C:7]1[CH:6]=[C:5]([CH2:4][C:5]([CH3:10])([CH3:6])[CH:4]=[O:1])[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: [OH-]
Reactant: Cc1ccc(CCl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(CC(C)(C)C=O)cc1F
Temperature: 70 °C

Procedure:
Under argon, a mixture of sodium hydroxide (2.8 g, 70 mmol) and tetrabutylammonium iodide (0.6 g, 1.6 mmol) in 8 ml benzene and 2.8 ml H2O was heated at 70° C. to form a homogeneous mixture. A mixture of the product of STEP 2 (10.5 g, 60.1 mmol) and isobutylaldehyde (5.76 g, 80 mmol) in 20 ml benzene was added to the above solution dropwise. The resulting reaction mixture was heated at 70-75° C. for 6 h. The product was extracted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=5/95) to yield a colorless oil in 7.3 g (58%). NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: COc1ccc(Br)c(O)c1
Product: COc1ccc(Br)c(OCC2CC2)c1

Procedure:
Starting from commercially available 2-bromo-5-methoxy-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)nc(N3CCCC3)c2cc1Oc1c(C)cccc1C

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass C25H25N5O3, 443.2.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([O:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>C(Cl)Cl>[CH2:72]([O:71][C:67]1[CH:66]=[C:65]([CH:70]=[CH:69][CH:68]=1)[CH2:64][C@H:50]([NH:49][C:11]([C:9]1[N:10]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[O:7][CH:8]=1)=[O:13])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1)[CH2:73][CH2:74][CH3:75]
Reactant: CCCCOc1cccc(C[C@H](N)[C@H](O)CNCc2cccc(CC)c2)c1
Reactant: CS(=O)(=O)Nc1nc(C(=O)O)co1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1cccc(C[C@H](NC(=O)c2coc(NS(C)(=O)=O)n2)[C@H](O)CNCc2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6 %

Procedure:
To a stirred solution of 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylic acid (43) (100 mg, 0.5 mmol) and HATU (180 mg, 0.5 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (100 μL, 0.6 mmol). In a separate flask, N,N-diisopropylethylamine (200 μL, 1.2 mmol) was added to amine 48 (135 mg, 0.3 mmol) in methylene chloride (2 mL). This solution was added to the above solution containing the acid and the resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 93:7 to 90:10 methylene chloride/methanol) provided N-{(1S,2R)-1-(3-butoxybenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide (50a) (10 mg): mp 78–80° C.; IR (KBr) 2960, 1602, 1581, 1490, 1450 cm−1; 1H NMR (500 MHz, CD3OD) δ 7.67 (s, 1H), 7.34–7.09 (m, 5H), 6.82–6.68 (m, 3H), 4.18 (s, 2H), 4.07–4.05 (m, 1H), 3.90–3.84 (m, 3H), 3.23–3.16 (m, 2H), 3.04 (s, 3H), 3.04–3.01 (m, 1H), 2.75–2.64 (m, 3H), 1.69–1.66 (m, 2H), 1.46–1.42 (m, 2H), 1.21 (t, J=8 Hz, 3H), 0.94 (t, J=8 Hz, 3H); ESI-MS m/z 559 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.1 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 ML). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (53%). white solid mp 207° C. , MS: 462.5 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][NH:37][C:38](=[O:39])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C(Cl)Cl>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([N:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][NH:37][C:38](=[O:39])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5cc[nH]c(=O)c5n(C5CCCC5)c4n3)nn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2c3cnc(Nc4ccc(N5CCNCC5)nn4)nc3n(C3CCCC3)c12

Procedure:
Compound 162 was treated with 1:1 TFA/DCM (2 mL) at room temperature for an hour. The solvent was evaporated. The residue was re-dissolved in 4 mLl methanol and purified on a C-18 reverse phase column (150×30 mm, 4 micro) using Mass directed preparative HPLC and gradient elution of acetonitrile in water containing 0.1% TFA to provide the title compound 161 as a TFA salt. LCMS retention time (minutes): 0.793. LCMS-ESI (POS), M/Z, M+1: 432.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:18](=O)[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:18][CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NC2CCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclobutylamino)-2-methylbenzoate (0.70 g, 2.73 mmol) and acetaldehyde (0.36 g, 8.20 mmol) in dichloroethane (15 mL), acetic acid (0.98 g, 16.4 mmol) was added and the reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (1.7 g, 8.2 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure to give title compound (0.71 g, 91%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][OH:13])=[CH:3][CH:4]=1
Reactant: C#CCCO
Reactant: Fc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(F)cc1
Reaction time: 5 h
Yield: 85.3 %

Procedure:
1 g of bis-(triphenylphosphine)-palladium(II) chloride, 3.8 g of copper(I) iodide and 8.7 g of triphenylphosphine were added in succession to a solution of 100 g of 4-bromofluorobenzene in 350 ml of triethylamine. This mixture was refluxed, after which 43.4 g of 3-butynol were added dropwise at this temperature (about 100° C.) in the course of 20 minutes. The mixture was stirred for a further 5 hours at this temperature. After the mixture had cooled, the triethylamine was distilled off. The residue was taken up in methyl tert-butyl ether and water. The aqueous phase was extracted twice with methyl tert-butyl ether, and the combined organic extracts were washed in succession with 1 N hydrochloric acid and with 10% strength sodium bicarbonate solution, dried over sodium sulfate and evaporated down in a rotary evaporator. Distillation under greatly reduced pressure gave 80 g (86%) of the desired compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:14]([CH2:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)Cc2ccc(F)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(Cc1ccc(F)cc1)C[C@@H]1CCNC1

Procedure:
Using a similar procedure to that described in Example 93, step 2, (3R)-1-(tert-butoxycarbonyl)-3-[(4-fluorobenzylsulfinyl)methyl}pyrrolidine (0.5149 g, 1.51 mmol) was reacted with trifluoroacetic acid (2ml) in dichloromethane (6ml) to give, after work up, 0.3447 g (95%) of the title compound as a white solid, which was used without further purification. δH (360 MHz, CDCl3) 1.57 (1H, m), 2.13 (1H, m), 2.54-2.72 (4H, m), 3.05 (2H, m), 3.27 (1H, m), 3.96 (2H, m), 708 (2H, t, J=8.6 Hz), 7.26-7.30 (2H, m).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1.CN([CH:24]=[O:25])C.OS(O)(=O)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:15]=1[CH:24]=[O:25]
Reactant: Brc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(Br)cccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To anhydrous THF (70 ml), diisopropylamine (8.3 ml, 59.34 mmol) was added and then n-BuLi (1.6 M, 59.34 mmol) was slowly added dropwise at 0° C. using a syringe in a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min, and the temperature thereof was cooled to −78° C. Subsequently, 1,3-dibromobenzene (7 g, 29.67 mmol) in THF (35 ml) was slowly added using a dropping funnel. The reaction mixture was stirred at −78° C. for 30 min, following the slow addition of DMF (4.6 ml, 59.34 mmol), and then continuously stirred for 1 hour. After the termination of the reaction, an aqueous solution of dilute H2SO4 was added, and the resulting solution was extracted two times with ethyl acetate, washed with a saturated NaCl solution, dried over anhydrous MgSO4, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=40:1), thus obtaining the title compound as a white solid (6.64 g, 25.16 mmol, 85%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A mixture of 4-chloro-3-nitrobenzaldehyde (1.00 g, 5.389 mmol), 4-(benzyloxy)phenol (1.187 g, 5.928 mmol), and potassium carbonate (0.744 g, 5.389 mmol) in anhydrous pyridine (10 mL) was heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 mL) and washed with 1N aqueous hydrochloric acid (2×50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel flash chromatography using methylene chloride as eluent provided the title compound as a yellow solid (1.625 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:14]=[C:13]([CH3:15])[N:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]=2[CH:23]=[O:24])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:14]=[C:13]([CH3:15])[N:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]=2[CH2:23][OH:24])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c(C=O)n1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(CO)n1-c1ccc(F)cc1

Procedure:
To a solution of 100 mg (0.29 mmol) 5-(2-Chloro-pyridin-4-ylethynyl)-3-(4-fluoro-phenyl)-2-methyl-3H-imidazole-4-carbaldehyde (example 26) in 5 ml of methanol were added at 0° C. 11 mg (0.29 mmol) of sodium borohydride, and the mixture was stirred for 1 h at 0° C. The reaction mixture was quenched with sat. NaHCO3− solution and evaporated. The residue was extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1). The desired compound was obtained as a white solid (40 mg, 40%), MS: m/e=342.1 (M+H+).
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1>CO.[O-2].[O-2].[Mn+4]>[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:1])=[O:15])=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: CC(=O)Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: COC(=O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 28 %

Procedure:
Acetyl chloride (5 mL) was added to an ice-cooled solution of 4-(hydroxymethyl)phenylacetic acid (5.78 g, 34.8 mmol) in methanol (200 mL). The reaction mixture allowed to warm to RT and stirred at this temperature for 42 hours. The solvent was evaporated at reduced pressure and the residue dissolved in DCM (100 mL). Manganese dioxide (29.47 g, 339 mmol) was added and the resultant suspension stirred at RT for 18 hours. The suspension was filtered through celite and the filter cake washed with further DCM. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0-25% ethyl acetate in iso-hexane to afford the title compound (1.72 g, 28%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=[O:8])=[CH:2]1.[CH3:10]O>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:2]1
Reactant: CO
Reactant: O=C(O)Cc1ccsc1
Product: COC(=O)Cc1ccsc1

Procedure:
Methyl 3-thienylacetate was prepared by heating 3-thienylacetic acid in acidic methanol. It is an oil, 1H nmr:delta 3.71 (2H, s), 3.76 (3H, s) ppm.