Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:7]=2[C:6]=1[CH:18]1[CH2:23][CH2:22][N:21](CC2C=CC=CC=2)[CH2:20][CH2:19]1)=[O:4].Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[CH3:35][O:34][C:32]([N:21]1[CH2:22][CH2:23][CH:18]([C:6]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:8]=3[S:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:19][CH2:20]1)=[O:33]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1C1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1C1CCN(C(=O)OC)CC1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 3-(1-benzyl-piperidin-4-yl)-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (5.9 g, 13.6 mmol) in DCM (50 mL) was added methyl chloroformate (1.26 mL, 16.3 mmol) drop-wise. The resulting solution was stirred overnight when the volatiles were removed in vacuo. The residue was washed with heptane to yield 4.2 g (77%) of the desired product as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([CH:19]=[O:20])[C:8]2=[O:21])(=[O:3])[CH3:2].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.[Cr](O)(O)(=O)=O>CC(C)=O.S(=O)(=O)(O)O.O>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19]([OH:24])=[O:20])[C:8]2=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2occ(C=O)c(=O)c2cc1OC(C)=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(C)=O

Procedure:
6,7-Diacetoxychromone-3-carboxaldehyde (17.8 g) was dissolved in acetone (1 liter). To this solution was added dropwise with stirring Jones reagent (32.8 ml) which had been previously prepared by dissolving chromic acid (133.6 g) in concentrated sulfuric acid (115 ml) diluted with water to a volume of 500 ml.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([CH3:6])[CH3:5].CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:45](=[O:46])[C:44]([CH2:47][CH2:48][CH:49]=O)=[C:43]([C:51]3[CH:56]=[CH:55][C:54]([S:57]([CH3:60])(=[O:59])=[O:58])=[CH:53][CH:52]=3)[CH:42]=[N:41]2)[CH:36]=[CH:37][C:38]=1[F:39]>C1(C)C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:45](=[O:46])[C:44]([CH2:47][CH2:48][CH:49]=[CH:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:43]([C:51]3[CH:56]=[CH:55][C:54]([S:57]([CH3:60])(=[O:58])=[O:59])=[CH:53][CH:52]=3)[CH:42]=[N:41]2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: CC(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2CCC=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CC=CCCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C

Procedure:
A mixture of isoamyltriphenylphosphonium bromide (414 mg, 1 mmol) and potassium t-butoxide (112 mg, 1 mmol) in toluene (25 mL) was refluxed for 30 minutes and then cooled to room temperature. The crude aldehyde was added and the mixture was refluxed for 14 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and was washed with water, 10% citric acid, brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica gel, 1:1 hexanes-ethyl acetate) provided the title compound as an oil (yield: 120 mg, 13%o) 1H NMR (300 MHz, DMSO-d6) δ 0.74 (d, J=7 Hz, 6H), 1.44 (m, 1H), 1.70 (t, J=7 Hz, 2H), 2.22 (m, 2H), 2.54 (m, 2H); 3.30 (s, 3H), 5.29 (m, 2H), 7.51 (m, 1H), 7.63 (m, 1H), 7.74 (d, J=9 Hz, 2H), 7.82 (m, 1H), 8.02 (s, 1H), 8.10 (d, J=9 Hz, 2H). MS (APCI+) nmz 473 (M+H)+ and (APCI−) m/z 471 (M−H)−, m/z 507 (M+Cl)−. Anal. calc. for C25H26F2N2O3S: C, 63.54; H, 5.54; N, 5.92. Found: C, 63.74; H, 5.67; N, 5.58.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:34][C:33]3[CH:35]=[CH:36][C:30]([CH2:29][NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:27])=[CH:31][CH:32]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 96.2 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and p-tert-butoxycarbonylaminomethylaniline (130 mg, 0.5 mmol) to give 230 mg of the title compound (80%): mp 156°~157° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (s, 1H), 9.98 (s, 1H), 7.48 (d, 2H, J=8.6 Hz), 7.34 (t, 1H, J=5,7 Hz), 7.24 (bs, 1H), 7.17 (bs, 1H), 7.15 (d, 2H, J=8.6 Hz), 5.16~5.26 (m, 1H), 4.06 (d, 2H, J=5.7 Hz), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.56~2.65 (m, 2H), 2.10 (dm, 1H, J=13.5 Hz), 1.81~1.96 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:18])[NH:15][CH2:16][CH2:17][C:12]=3[C:11]([C:19]#[N:20])=[N:10]2)=[CH:5][CH:4]=1.I[C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:37])([CH3:36])[CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][C:31]2=[O:35])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I>[CH3:37][C:28]([C:25]1[CH:24]=[CH:23][C:22]([N:15]2[CH2:16][CH2:17][C:12]3[C:11]([C:19]#[N:20])=[N:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[C:14]2=[O:18])=[CH:27][CH:26]=1)([CH3:36])[CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35]
Reactant: COc1ccc(-n2nc(C#N)c3c2C(=O)NCC3)cc1
Reactant: CC(C)(CN1CCCC1=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2nc(C#N)c3c2C(=O)N(c2ccc(C(C)(C)CN4CCCC4=O)cc2)CC3)cc1
Temperature: 130 °C

Procedure:
To 1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (0.149 g, 0.55 mmol), 1-[2-(4-iodo-phenyl)-2-methyl-propyl]-pyrrolidin-2-one (0.19 g, 0.55 mmol), and K2CO3 (0.23 g, 1.7 mmol) was added degassed DMSO (4 mL) followed by CuI (21 mg, 0.11 mmol). The mixture was heated to 130° C. for 5 h. The reaction was cooled, partitioned between ethyl acetate and water, extracted with ethyl acetate, and dried (MgSO4). Chromatography on silica gel using 0–5% MeOH in CH2Cl2 followed by further purification by HPLC afforded the title
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=3)[N:15]=[N:14]2)=[CH:10][CH:9]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:24][C:22]3[CH:23]=[C:18]([C:16]4[N:15]=[N:14][N:13]([CH2:12][C:11]5[CH:26]=[CH:27][C:8]([Cl:7])=[CH:9][CH:10]=5)[CH:17]=4)[CH:19]=[CH:20][C:21]=3[CH3:25])[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cc1ccc(-c2cn(Cc3ccc(Cl)cc3)nn2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (1.11 g, 3.41 mmol), 5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenol (0.75 g, 2.50 mmol) (from Example 34 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 23 mL) was heated at 70° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.76 g, 2.27 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The precipitate was filtered, washed with ethyl acetate and dried to give 4-chloro-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.33 g, 26%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[NH:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2cc3ccccc3c(=O)[nH]2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Temperature: 130 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
3-(5-Methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one (7.4 g, 0.03 mol) and POCl3 (80 ml) were sealed in 4 bottles (20 ml). The mixture was heated at 130° C. for 15 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 15 ml MeOH. The mixture was stirred for 2 hours at room temperature, and the solid was collected and dried to give desired product (4.7 g, 61% yield). LC-MS: 259 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([C:25]([CH:27]1[CH2:29][CH2:28]1)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].CS(C)=O.O>C(O)C.CO>[CH:27]1([C:25]2[N:12]=[C:7]3[C:6]([O:5][CH2:4][C:3]4[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:2]=4[F:1])=[CH:11][CH:10]=[CH:9][N:8]3[C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:29][CH2:28]1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C(=O)C1CC1
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c(C2CC2)nc2c(OCc3c(F)cccc3F)cccn12

Procedure:
1.69 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 7.13 mmol, 1 equivalent) were initially charged in 44.4 ml of ethanol, and 425 mg of powdered molecular sieve 3 Å and 6.8 g of ethyl 2-chloro-3-cyclopropyl-3-oxopropanoate (crude product from Example 23A) were added. The reaction mixture was heated at reflux for 48 h and then concentrated under reduced pressure, and the residue was chromatographed (cyclohexane/ethyl acetate as mobile phase). The product-containing fractions were combined and concentrated under reduced pressure. The residue obtained in this manner was taken up in methanol, DMSO and water. The solid obtained was filtered off and dried under high vacuum. This gave 410 mg (15.4% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10](=[O:19])[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:20][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)cc(-c2ccc(Cl)cc2)o1
Temperature: 0 °C

Procedure:
A solution of ethyl 6-(4-chlorophenyl)-2,4,6-trioxohexanoate (0.26 g) in cold concentrated sulphuric acid (3 ml) was stirred for 3 hours at 0°-5° C. then poured on to ice (10 g). The solid product was recrystallised from ethanol-water to give the title product identical (mp, IR and NMR, and thin-layer chromatography) with the product described in Example 12.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O)#[N:23].O[NH:38][C:39]([C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH2:50][OH:51])=[CH:44]2)=[NH:40]>CN(C=O)C.CCOC(C)=O>[OH:51][CH2:50][C:45]1[NH:46][C:47]2[C:43]([CH:44]=1)=[CH:42][C:41]([C:39]1[N:40]=[C:27]([C:26]3[CH:30]=[CH:31][C:32]([O:33][CH:34]([CH3:36])[CH3:35])=[C:24]([CH:25]=3)[C:22]#[N:23])[O:29][N:38]=1)=[CH:49][CH:48]=2
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1ccc2[nH]c(CO)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CO)cc4c3)no2)cc1C#N
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848, 144 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 15 min. N-hydroxy-2-(hydroxymethyl)-1H-indole-5-carboximidamide (D25) (144 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 4 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was crystallized from EtOAc/ether to afford 5-{3-[2-(hydroxymethyl)-1H-indol-5-yl]-1,2,4-oxadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile (D26) (70 mg) as a pale brown solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 4.65 (2H, d), 4.99 (1H, m), 5.36 (1H, t) 6.46 (1H, s), 7.50 (1H, d), 7.56 (1H, d), 7.79 (1H, dd), 8.28 (1H, s), 8.43 (1H, dd), 8.51 (1H, d), 11.43 (1H, s). MS (ES): C21H18N4O3 requires 374; found 375.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile in a manner analogous to Example 1221d. Product was isolated as an off-white solid (298 mg, 36%), MP=99-100, LCMS 479.23 (M+H), HPLC purity 99%, 1H-NMR (CDCl3, 400 MHz) δ 8.45 (d, J=7.6 Hz, 1H), 8.08 (s, 1H), 7.62 (s, 1H), 7.38-7.33 (m, 2H), 7.21 (d, 8.0 Hz, 1H) 7.13-7.72 (m, 4H), 4.87 (s, 2H), 3.56 (t, J=5.7 Hz, 2H), 3.39 (s, 3H), 2.97-2.90 (m, 4H), 2.79-2.2.73 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]([C:24](O)=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(COC)OC.O>[OH:25][CH2:24][C@H:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
(2R)-4-[(Benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.4 g, 3.9 mmol) was dissolved in dimethoxyethane (10 mL) and to the cooled resultant solution was added N-methylmorpholine (0.4 g, 3.9 mmol) followed by isobutyl chloroformate (0.54 g, 3.9 mmol) by means of drops. The mixture was stirred at 0° C. for 20 min and then the mixture was filtered. The filtrate was transferred to a 500 mL flask and then cooled again. Sodium borohydride (0.22 g, 5.9 mmol) dissolved in water (5 mL) was added and the external cooling bath was removed. The reaction mixture was stirred until the temperature of it had reached RT whereupon water (120 mL) was added. The mixture was extracted trice with ethyl acetate and the combined organic solutions were dried and then evaporated. The product was purified by column chromatography on silica gel (ethyl acetate-heptane 10% to 70%). There was obtained 1.2 g (84%) of 4-benzyl 1-tert-butyl (2R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.4 (s, 9H), 2.7-3.2 (b, 4H), 3.5 (b, 2H), 3.8-4.2 (m, 4H), 5.1 (m, 2H), 7.2-7.4 (m, 5H); LCMS: m/z 349 (M−1)−.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([C:13](O)=[O:14])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([CH2:10][OH:11])[CH2:13][OH:14])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CC(CO)(CO)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 19 h

Procedure:
4.00 g (10.69 mmol) 2,2-bis(4-nitrobenzyl)malonic acid are dissolved in 40 ml tetrahydrofuran and added dropwise in a the course of 2 hours to 64.1 ml (64.1 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydrofuran. After 19 hours at 25° C., 50 ml water are carefully added. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue, 3.77 g (97%) of 2,2-bis(4-nitrobenzyl)-1,3-propandiol as white powder is used without further purification.
Reaction SMILES: C([S:4][CH2:5][CH:6]([C:17]([F:20])([F:19])[F:18])[C:7]([NH:9][CH2:10][CH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1)=[O:8])(=O)C.O.Cl>[NH4+].[OH-]>[F:19][C:17]([F:18])([F:20])[CH:6]([CH2:5][SH:4])[C:7]([NH:9][CH2:10][CH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1)=[O:8]
Reactant: CC(=O)SCC(C(=O)NCCc1nnn[nH]1)C(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCc1nnn[nH]1)C(CS)C(F)(F)F
Temperature: 0 °C
Yield: 65 %

Procedure:
The title compound of Example 26 (1.0 g., 3.2 mmol.) was dissolved at 0° C. under argon in 2.5 mL of a 1:1 concentrated NH4OH:H2O solution. The reaction mixture was stirred at 0° C. for minutes and then acidified with 5N HCl to pH 6 at 0° C. The product was extracted with ethyl acetate containing 5 percent methanol (3×) (200 mL portions). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed through 50 g of Merck silica gel using a (3:3:94) methanol:acetic acid:methylene chloride solvent system. The appropriate fractions were combined and concentrated to yield 0.56 g of the title product, m.p. 182°-184° C.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>COC(C)(C)C>[CH3:9][S:10]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:12])=[O:11]
Reactant: C#CC(O)(CF)CF
Reactant: CS(=O)(=O)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: C#CC(CF)(CF)OS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and methanesulfonyl chloride (0.85 ml) were dissolved in tert-butyl methyl ether (15 ml); to the solution under cooling with ice, triethylamine (1.5 ml) was added dropwise in a nitrogen atmosphere. After stirring for 1.5 hours under cooling with ice, tert-butyl methyl ether was added to the reaction mixture, which was then washed with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (1.9 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>CCCCCC.C(OCC)(=O)C>[C:10]([CH2:12][C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[CH3:9])=[O:14])#[N:11]
Reactant: CCOC(=O)CC#N
Reactant: Cc1cc(F)ccc1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1NC(=O)CC#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
4-Fluoro-2-methylaniline (3.9 g, 31 mmol) was added to ethyl cyanoacetate (5.3 g, 46 mmol) and the mixture was stirred at 150° C. for 4 hr. After cooling to room temperature, hexane-ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (4.0 g, 67%) as a pale-yellow solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:13][C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH2:22][N:21]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:20]2)[S:17][CH:18]=1>CN1CCCC1=O>[CH2:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:23]2[CH2:24][CH:19]([C:16]3[S:17][CH:18]=[C:14]([CH2:13][NH:4][CH:1]([CH3:3])[CH3:2])[N:15]=3)[CH2:20][N:21]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:22]2)=[CH:30][CH:29]=1)[CH3:32]
Reactant: CC(C)N
Reactant: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCc1ccc(C2CC(c3nc(CNC(C)C)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
24 mg (0.411 mmol) of isopropylamine and 70 mg (0.685 mmol) of triethylamine were added to a solution of 119 mg (0.274 mmol) of the compound from Example 141A in 2 ml of N-methylpyrrolidone. The reaction mixture was stirred at 80° C. overnight and, without any further work-up, purified by preparative HPLC. Yield: 10 mg (8% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:30][C:31]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([CH:40]([CH3:42])[CH3:41])[O:33][N:32]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:30][C:31]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([CH:40]([CH3:42])[CH3:41])[O:33][N:32]=1
Reactant: Cc1cccc(C)c1O
Reactant: COC(=O)c1c(CO)noc1C(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(COc2c(C)cccc2C)noc1C(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 2,6-dimethylphenol (184 mg, 1.51 mmol), triphenylphosphine (396 mg, 1.51 mmol), and methyl 3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (300 mg, 1.51 mmol) in toluene (4 mL) was slowly added diisopropyl azodicarboxylate (0.272 mL, 1.51 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes and then allowed to stand at ambient temperature overnight. The solution was concentrated and purified by chromatography (silica gel, 2.5% acetone in hexanes) to afford methyl 3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (329 mg, 72%). 1H-NMR (400 MHz, DMSO-d6) δ 7.02-6.90 (m, 3H), 5.00 (s, 2H), 3.74 (s, 3H), 3.72 (septet, J=7 Hz, 1H), 2.17 (s, 6H), 1.28 (d, J=7 Hz, 6H).