Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](N2C3C(=CC=CC=3)C=C2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.IC1C=CC=C(C)C=1>>[CH3:43][CH:41]([CH3:42])[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[N:17]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:18]=[CH:19]4)[CH2:28][CH2:29]2)[CH:34]=1)=[O:44]
Reactant: Cc1ccc(-n2ccc3ccccc32)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Agent: Cc1cccc(I)c1
Product: Cc1cccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)c1
Yield: 60 %

Procedure:
According to the procedure used for the synthesis of 1-(4-methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100 mmol) and 1-iodo-3-methylbenzene (43.6 mg, 0.200 mmol) gave the desired product (28 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.68–6.60 (m, 14H), 3.66 (s, 2H), 3.16–2.96 (m, 2H), 2.59–2.44 (m, 2H), 2.44 (s, 3H), 2.18–2.01 (m, 2H), 1.91–1.68 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[NH2:12][C:13]([NH2:15])=[S:14]>CO>[ClH:1].[C:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:14][C:13](=[NH:12])[NH2:15])=[CH:4][CH:5]=1)#[N:11]
Reactant: N#CCc1ccc(CCl)cc1
Reactant: NC(N)=S
Solvent: CO
Product: Cl
Product: N#CCc1ccc(CSC(=N)N)cc1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
The 4-chloromethylphenylacetonitrile (200 mg, 1.21 mmol) and thiourea (101 mg, 1.33 mmol) were mixed in 1 ml of methanol. The mixture was heated to reflux for 3 to 4 hours. The reaction mixture was evaporated. After that, 1 ml of methanol and 4 ml of acetone were added and the mixture was stirred for one hour. The crystalline material was filtered and the product was dried under high vacuum overnight to yield 219 mg (0.91 mmol, yield 75%) of product as off white crystals, with purity greater than 95%. 1H NMR (300 MHz, d6-DMSO) 4.03 (s, 2H), 4.50 (s, 2H), 7.35 (d, 2H, J=8.23 Hz), 7.45 (d, 2H, J=8.23 Hz), 9.22 (s, 4H). (M+H) 206.00
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([O:23][CH2:24][CH3:25])(=[O:22])[C:15]#[C:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClC1C=CC=C(Cl)C=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:14]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: O=c1oc(-c2ccc(Cl)cc2)ns1
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1snc(-c2ccc(Cl)cc2)c1C(=O)OCC
Temperature: 148 °C
Reaction time: 16 h

Procedure:
Into a 150-mL sealed tube, was placed 5-(4-chlorophenyl)-2H-1,3,4-oxathiazol-2-one (2 g, 9.65 mmol, 1.00 equiv), 1,4-diethyl but-2-ynedioate (3.29 g, 19.33 mmol, 2.00 equiv), 1,3-dichlorobenzene (30 mL). The resulting solution was stirred for 16 h at 148° C. The resulting mixture was concentrated under vacuum. This resulted in 1 g (31%) of 4,5-diethyl 3-(4-chlorophenyl)-1,2-thiazole-4,5-dicarboxylate as brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C@@:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C@@:5]12[C:21]([F:23])([F:22])[CH2:20][O:19][C:18]([NH2:24])=[N:17]1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)[OH:33])[CH:29]=[N:30][CH:31]=1>>[CH:20]([OH:19])=[O:33].[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C@@:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C@@:5]23[C:21]([F:23])([F:22])[CH2:20][O:19][C:18]([NH2:24])=[N:17]2)[CH:29]=[N:30][CH:31]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: NC1=N[C@@]2(C[C@]3(CCCOC3)Oc3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(C[C@]3(CCCOC3)Oc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Product: O=CO
Yield: 66 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2′S,4R)-6′-bromo-5,5-difluoro-5,5″,6,6″-tetrahydro-4″H-dispiro[1,3-oxazine-4,4′-chromene-2′,3″-pyran]-2-amine (intermediate B6.8) with 5-chloropyridin-3-ylboronic acid and chromatography on preparative HPLC yielded the title compound (66% yield) as an off-white, amorphous material. MS (ISP): m/z=436 [M+H]+ and 438 [M+2+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/B(O)O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][C:3]=2[CH3:20])=[CH:24][CH:23]=1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2C(N)=O)ccc1Br
Reactant: OB(O)/C=C/c1ccc(F)cc1
Product: Cc1cc(S(=O)(=O)c2ccccc2C(N)=O)ccc1/C=C/c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-[(4-bromo-3-methylphenyl)sulfonyl]benzamide (Step 1) and [(E)-2-(4-fluorophenyl)vinyl]boronic acid according to the method of Example 1 Step 4. m/z (ES+) 379 [(M−NH2)+].
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:27]12[C:35](=[O:36])[O:34][C:32](=[O:33])[C:28]=1[CH2:29][CH2:30][CH2:31]2.O.Cl>CN(C)C=O.C(O)C>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:35]([C:27]2[CH2:31][CH2:30][CH2:29][C:28]=2[C:32]([OH:34])=[O:33])=[O:36])[N:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: O=C1OC(=O)C2=C1CCC2
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.4 %

Procedure:
In 30 ml of N,N-dimethylformamide, 3.63 g of 5-ethyl-2-imino-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3,4-thiadiazoline was dissolved, followed by the addition of 1.44 g of 1-cyclopentene-1,2-dicarboxylic anhydride. The resulting mixture was stirred at room temperature for 6 hours. To the reaction mixture, 200 ml of water and 5 ml of hydrochloric acid were added. The powders so precipitated were collected by filtration. The powders so obtained were suspended in 100 ml of ethanol and the resulting suspension was heated under reflux for 20 minutes. The powders were collected by filtration, washed successively with ethanol and diethyl ether and then dried, whereby 4.53 g of the title compound was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.C(O)(C)C.O>C1(C)C=CC=CC=1>[CH3:13][C:8]1([C:5]2([CH2:3][OH:2])[CH2:7][CH2:6]2)[O:9][CH2:10][CH2:11][O:12]1
Reactant: COC(=O)C1(C2(C)OCCO2)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C2(CO)CC2)OCCO1
Temperature: 0 °C

Procedure:
11.2 g of 5 is dissolved in 150 ml of toluene and cooled under nitrogen to 0° C. 125 ml of DIBAH solution (1.2 M in toluene) is now slowly added in drops and stirred for 2 more hours. Then, 1.25 ml of isopropanol and 25 ml of water are added in drops and stirred overnight. The precipitate is filtered off, the filtrate is concentrated by evaporation and chromatographed on silica gel with ethyl acetate/hexane, whereby 9.1 of title compound 6 accumulates as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][OH:18]>C(O)C.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=[N:17][OH:18])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Solvent: CCO
Solvent: O
Product: ON=C1C2CCC1CN(Cc1ccccc1)C2
Yield: 68 %

Procedure:
To a solution of the title compound of Step A (6.6 g, 30.7 mmol) in ethanol (80 ml) was added hydroxylamine (3.6 ml of a 50% Wt solution in water, 42.9 mmol) and the resulting mixture heated at reflux for 4 h. The cooled reaction mixture was evaporated and the residue triturated with hexanes, filtered and dried to afford the title compound 4.8 g (68%) as a white solid. 1H NMR (CDCl3): 1.76 (m, 2H), 1.97 (m, 2H), 2.40 (d, J 10.1 Hz, 2H), 2.56 (s, 1H), 2.84 (dd, J 10.3 and 3.7 Hz, 1H), 2.91 (dd, J 10.1 and 3.0 Hz, 1H), 3.35 (s, 1H), 3.57 (s, 2H), 7.29 (m, 1H), 7.35 (m, 4H), 8.49 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([NH2:12])[CH:3]=1.BrC1C=C(N2[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][N:22]=[N:21]2)C=CC=1OC>>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([N:12]2[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][N:22]=[N:21]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N)cc2o1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1Br
Product: Cc1nc2c(Br)cc(-n3nnnc3C(F)(F)F)cc2o1

Procedure:
Compound was prepared according to the procedure given in Example 6, Step F (b & c) using 4-bromo-2-methyl-6-amino-benzooxazole in place of 2-Bromo-4-(trifluoroacetamido)anisole and 2-Bromo-4-(5-(trifluoromethyl)tetrazol-1-yl)anisole.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[C:27]([C@@H:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=1)#[N:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][C@H:29]([C:27]#[N:28])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:31]=1)=[O:24]
Reactant: C=C=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
1.22 g of dicyclohexylcarbodiimide and a few crystals of 4-dimethylamino-pyridine were added at 0° C. to a solution of 900 mg of (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)cyclopropane-carboxylic acid in 20 ml of methylene chloride and the mixture was stirred at 0° C. for 15 minutes. A solution of 1.46 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 7 ml of methylene chloride was added to the mixture which was stirred for 5 hours at 20° C. and then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 6-4 and then a 7-3 benzene-petroleum ether (b.p.=35° to 70° C.) mixture yielded 754 mg of (S)α-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-25° (c=0.7% in chloroform).
Reaction SMILES: C(Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.ICCCCC.[CH3:15][C:16]1[N:17]=[C:18]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[S:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:15][C:16]1[N:17]=[C:18]([N:26]2[CH2:30][CH2:29][N:28]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:2])[C:27]2=[O:31])[S:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccccc1
Solvent: CCCCCI
Product: CCCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Yield: 69 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 1-iodopentane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 69% yield: 1H NMR (300 MHz, CDCl3) δ 4.23 (q, J=7.2 Hz, 2H), 4.11-3.87 (m, 2H), 3.64-3.43 (m, 2H), 3.26 (t, J=7.5 Hz, 2H), 2.63 (s, 3H), 1.61-1.18 (m, 9H), 0.74 (t, J=7.2 Hz, 3H); MS (ES+) m/z 326.3 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:14]=[CH:13][NH:12][C:6]=2[N:7]=[C:8]([S:10][CH3:11])[N:9]=1.[CH2:15]([O:22][C@H:23]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:25][C@@H:24]1Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[Cl:3][C:4]1[C:5]2[CH:14]=[CH:13][N:12]([C@@H:24]3[O:25][C@H:26]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:27]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:23]3[O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[N:7]=[C:8]([S:10][CH3:11])[N:9]=1
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CSc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3.1 g sodium hydride, 25.9 g of 4-chloro-2-methylmercapto-7H-pyrrolo[2,3-d]pyrimidine, and 250 ml of dry dimethylformamide (DMF) is stirred at 50° C. for 0.5 hour, cooled, and added to 62.8 g of 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride. The solution is stirred at ambient temperature for 15 hours, concentrated in vacuo, and distributed between a mixture of ethyl acetate and water. Chromatrography of the dried (MgSO4) layer over silica gel with 4:1 toluene-ethyl acetate provides 76 g of yellow, syrupy 4-chloro-2-methylmercapto-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13](=[S:15])[NH:12][C:11]=2[CH:16]=1)[CH3:6])C.[OH-].[Na+].C(O)(=O)C>CCO.O>[S:15]=[C:13]1[NH:12][C:11]2[CH:16]=[C:7]([CH:5]([CH3:6])[C:4]([OH:17])=[O:3])[CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-(2-Thioxo-2,3-dihydro-benzooxazol-5-yl)-propionic acid ethyl ester (124 mg) in 90% aq. EtOH was added NaOH (102 mg) at room temperature. After stirred for 20 h at 45, the reaction mixture was cooled to room temperature, diluted with water. The resulting aqueous layer was acidified with acetic acid and then extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. (105 mg, 95.4%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=[N:30][OH:31])[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Yield: 79.8 %

Procedure:
1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethanone (0.87 g, 2 mmol), hydroxylamine hydrochloride (0.28 g, 2.05 mmol) and sodium acetate (0.33 g, 2.06 mmol) were dissolved in ethanol (9.0 mL) and heated to reflux for 2 h. After cooling to ambient temperature water (20 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (silica gel, ethyl acetate) to yield the title compound as a colorless foam (0.74 g, 82%). ES-MS m/e: 437.5 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[CH:10][N:11]([CH3:12])[C:7]=2[CH:6]=[C:5]([C:13]2[CH:35]=[CH:34][C:16]([O:17][CH2:18][CH2:19][C:20]3([F:33])[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[C:15]([C:36]([F:39])([F:38])[F:37])[CH:14]=2)[N:4]=1)#[N:2].C(#N)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].C(Cl)[Cl:51]>>[ClH:51].[F:33][C:20]1([CH2:19][CH2:18][O:17][C:16]2[CH:34]=[CH:35][C:13]([C:5]3[N:4]=[C:3]([C:1]#[N:2])[C:8]4[N:9]=[CH:10][N:11]([CH3:12])[C:7]=4[CH:6]=3)=[CH:14][C:15]=2[C:36]([F:37])([F:38])[F:39])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:45]([OH:47])([C:44]([F:49])([F:48])[F:43])=[O:46]
Reactant: ClCCl
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4(F)CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cl
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4(F)CCNCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl 4-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-4-fluoropiperidine-1-carboxylate (0.7 g) in DCM (15 ml) was added acetonitrile (10 ml), followed by trifluoroacetic acid (10 ml). The mixture was stirred at room temperature for 10 minutes, then solvent and excess TFA were removed under vacuum. The residue was taken into ethyl acetate (15 ml), and diethylether (20 ml) was then added. The white precipitate product was then collected by filtration to give desired product as a TFA salt (0.7 g). 50 mg of this TFA salt was then converted to free base by means of SCX, then to HCl salt by treating with 2M HCl in ether. 1H NMR (CD3OD) δ: 8.60 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8.40 (d, 1H), 7.39 (d, 1H), 4.40 (t, 2H), 4.05 (s, 3H), 3.2-3.5 (m, 4H), 2.2-2.4 (m, 4H), 2.0-2.2 (m, 2H). MS m/z 448 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[FH:18].N([O-])=O.[Na+]>>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([F:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a steel bomb were combined 4-tert-butyl aniline (1 eq) and 70% hydrogen fluoride-pyridine (25 g/gm aniline). Sodium nitrite (1.5 eq) was then added portion wise over 5 minutes. The resulting solution was allowed to stir for 1 h at room temperature and then the bomb was sealed and heated at 85° C. for 1 h. Solution was then quenched with water/ice and extracted with ethyl ether. Organics washed with brine and dried with sodium sulfate and concentrated to afford 1-tert-butyl-4-fluorobenzene.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[N:25]=[C:26]([CH3:35])[N:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:28]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:44])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[N:25]=[C:26]([CH3:35])[N:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:28]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:10][CH2:11]2)[CH2:6]1)#[N:2]
Reactant: Cc1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)cn3COCC[Si](C)(C)C)cn1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CC(C#N)C4)C4CC4)c3n2)cn1-c1ccccc1
Yield: 61.9 %

Procedure:
2-(2-Methyl-1-phenyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (68 mg, 0.111 mmol) was dissolved in 0.6 mL of dichloromethane and then stirred in an ice bath. Trifluoroacetic acid (0.4 mL) was added slowly and the ice bath was removed. The reaction was stirred for 3 h and then cooled in ice bath. Sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in 4 mL of absolute ethanol, sodium acetate (183 mg) was added and the mixture was stirred for 20 h at 60° C. The reaction was cooled, and water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 33 mg (62%) of 2-(2-methyl-1-phenyl-1H-imidazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+H)+=481; mp=175-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[CH:11]=[N:10]1.C(N(CC)CC)C.CCOC(C)=O.[Br:41][CH2:42][CH2:43]Br>>[Br:41][CH2:42][CH2:43][N:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]2[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[CH:11][C:12]=2[CH:25]([CH3:27])[CH3:26])=[CH:17][C:18]=1[CH3:24])[CH3:23]
Reactant: BrCCBr
Reactant: CNc1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N(C)CCBr
Temperature: 90 °C
Yield: 37 %

Procedure:
To an ambient temperature solution of {4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amine (1.12 g, 2.77 mmol) in 1,2-dibromoethane (5 mL) is added triethylamine (1.54 mL, 11.08 mmol). The reaction is heated to 90° C. overnight. EtOAc is added to the reaction mixture. The resultant mixture is washed with brine, dried (MgSO4), and chromatographed (0% to 20% EtOAc/Hex) to yield the title compound (520 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.43-7.40 (m, 2H), 7.31 (dd, 1H, J=9.0, 7.1 Hz), 6.93 (d, 1H, J=7.3 Hz), 6.61-6.54 (m, 2H), 4.77 (s, 2H), 3.34 (t, 2H, J=6.5 Hz), 3.26 (t, 2H, J=6.7 Hz), 2.99 (sept, 1H, J=7.0 Hz), 2.65 (s, 3H), 2.26 (s, 3H), 1.30 (d, 6H, J=7.0 Hz).
Reaction SMILES: C1COCC1.[F:6][CH:7]([F:20])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][CH3:19].[Li][N:22]([Si](C)(C)C)[Si](C)(C)C.[CH3:31][S:32]([CH3:35])(=[O:34])=[O:33]>CO>[F:6][CH:7]([F:20])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([NH2:22])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:11][C:10]=1[O:17][CH2:18][CH3:19]
Reactant: CS(C)(=O)=O
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: CCOc1cc(C=O)ccc1OC(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
To the THF solution (100 ml) of 4-difluoromethoxy-3-ethoxy-benzaldehyde (21.0 g, 0.1 mol) was added dropwise LiN(TMS)2 (1M in THF, 100 ml, 0.1 mol) at 0° C. After 15 minutes of stirring, BF3 THF complex (22 ml, 0.2 mol) was added to the reaction mixture (1). To the THF solution (100 ml) of methyl sulfone (9.4 g, 0.1 mol) was added LiN(TMS)2 (1M in THF, 100 ml, 0.1 mol) at −78° C. The mixture (2) was stirred at −78° C. for 1 hour. Mixture (1) was added to the mixture (2) via a 2-way needle. The mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. MeOH (20 ml) was added to quench the reaction. The mixture was concentrated in vacuo until there was one-fourth left. To the resulted mixture was added HCl aqueous solution (20%, 150 ml) followed by concentrated HCl until pH=3. The mixture was extracted with ether (100 ml×3). The aqueous layer was neutralized with NaOH (15 M) till pH=8. The mixture was extracted with methylene chloride (100 ml×3). The combined organic layer was washed with water (100 ml×2), brine (100 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel column to give 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (2.8 g, 10%) as yellow oil. 1H NMR (CDCl3) δ 1.41 (t, J=6.8 Hz, 3H, OCH2CH3), 3.30-3.40 (m, 2H, CH2SO2), 3.45 (s, 3H, CH3), 4.58-4.64 (m, 1H, CHN), 6.53 (t, J=75 Hz, 1H, CF2H), 6.84-7.12 (m, 3H, Ar).