Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1>O.Cl>[NH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)[NH2:1]
Reactant: N#CCc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(NN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium nitrite (1.9 g) in water (16 ml) was added dropwise to a suspension of 4-aminophenylacetonitrile (3.6 g) in concentrated hydrochloric acid (37 ml) so that the temperature did not exceed +2° C. The resulting mixture was stirred overnight (room temperature), the yellow solid collected, washed with cold ethanol (20 ml) and ether (50 ml), dried (vacuum) to give the title compound as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[O:25][CH2:26][C@@H:27]([O:37][CH2:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])[CH2:28][O:29]CC2C=CC=CC=2)=[C:18]([O:47][CH3:48])[N:17]=1)=O)(C)(C)C.ClCCl.CO>ClCCl.[Pd]>[NH2:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[O:25][CH2:26][C@@H:27]([O:37][CH2:38][P:39]([O:41][CH2:42][CH3:43])([O:44][CH2:45][CH3:46])=[O:40])[CH2:28][OH:29])=[C:18]([O:47][CH3:48])[N:17]=1
Reactant: CCOP(=O)(CO[C@@H](COCc1ccccc1)COn1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)OCC
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOP(=O)(CO[C@@H](CO)COn1cnc2c(OC)nc(N)nc21)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
Trifluoroacetic acid (2 ml) was added to an ice cooled solution of (S)-2-[bis-(t-butoxycarbonyl)amino]-9-[3-benzyloxy-2-(diethoxyphosphorylmethoxy]propoxy]-6-methoxypurine (1.65 g, 2.3 mmol) in dry dichloromethane (30 ml) an the resulting solution left for 2 hours. After warming to ambient temperature, 10% Pd-C (800 mg) was added and the mixture hydrogenated at ambient temperature and pressure for 2 hours. The reaction mixture was filtered, the catalyst washed with dichloromethane (20 ml), the filtrate washed with saturated aqueous sodium bicarbonate solution, brine, dried (MgSO4) and evaporated to leave a colourless viscous oil. Chromatography of the oil on silica gel using dichloromethane/methanol 95:5 as the initial eluant, then changing the eluant to dichloromethane/methanol 90:10 gave (S)-2-amino-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy]-6-methoxypurine as a colourless oil (0.65 g, 67%). IR: νmax (film) 3360, 3230, 2990, 2940, 2910, 1620, 1585, 1500, 1485, 1455, 1390, 1335, 1265, 1240, 1165, 1120, 1060, 1025, 975, 825, 785 cm-1. 1H NMR: δH [(CD3)2SO] 1.23 (6H, t, J=7 Hz, (OCH2CH3)2), 3.45-3.60 (2H, m, collapses to d on D2O exchange, CH2OH), 3.70-3.85 (1H, m, CH), 3.96 (3H, s, OCH3), 3.9-4.15 (6H, m, (OCH2CH3, OCH2P), 4.31 (1H, dd, J=11.3 Hz, J=6.9 Hz, NOCHB), 4.45 (1H, dd, J =11.3 Hz, J=3 Hz, NOCHA), 4.84 (1H, t, J=5.5 Hz, D2O exchangeable OH), 6.59 (2H, br.s, D2O exchangeable NH2), 8.14 (3H, s, H-8). m/z: (FAB, thioglycerol matrix) 406 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)=[CH:14][CH:13]=2)[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[CH2:23](N)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:22]=[N:21][NH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:9][NH:10][CH2:11][CH3:23])=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Product: CCNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedures described in Examples 42A through to 42C but substituting methylamine for ethylamine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.11 [M+H]+ 326. 1H NMR (Me-d3-OD) δ 1.15 (3H, t), 2.83 (2H, q), 3.35-3.43 (2H, m), 4.25 (1H, t), 7.30-7.48 (6H, m), 7.57 (2H, d), 7.95 (2H, s).
Reaction SMILES: Cl.[S:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[C:7](=[S:9])=[S:8].C([O-])(=O)C.[Zn+2:14].C([O-])(=O)C>N1C=CC=CC=1>[S:2]1[CH2:6][CH2:5][N:4]([C:7]([S-:9])=[S:8])[CH2:3]1.[S:2]1[CH2:6][CH2:5][N:4]([C:7]([S-:9])=[S:8])[CH2:3]1.[Zn+2:14]
Reactant: S=C=S
Reactant: C1CSCN1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: c1ccncc1
Product: S=C([S-])N1CCSC1

Procedure:
While cooling and stirring 250 g. of pyridine, 175 g. (1.40 moles) of thiazolidine hydrochloride [preparation described by S. Ratner and H. Clarke, J. Am. Chem. Soc. 59, 200 (1937)] was added. After it had dissolved, 106.4 g. (1.40 mole) of carbon disulfide was added dropwise, followed by 128.5 g. (0.70 mole) of anhydrous zinc acetate. The resulting reaction mixture was stirred at 40° - 50°C for 2 hours. The precipitate was filtered at 5° - 10°C. The crude solid was water-washed and finally freed of pyridine by vacuum-drying at 120°C. to give 147.8 g. of the desired product. It gradually decomposed starting at ca. 200°C without a definite final decomposition point. A small sample washed with hot benzene had the following analysis:
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([O:34][CH3:35])=[O:33].C(OCC)(=O)C>CN(C=O)C.O>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:31]([C:32]([O:34][CH3:35])=[O:33])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:20][CH2:19]2)[CH:5]=1
Reactant: c1cc2[nH]cc(CCCC3CCNCC3)c2cc1-n1cnnc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCC(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl]piperidine (Description 2, 0.800 g, 0.0026 mol) was dissolved in anhydrous DMF (10 ml), under N2, and potassium carbonate (0.540 g, 0.0039 mol) added followed by (±)-methyl α-bromophenylacetate (Aldrich, 0.5 ml, 0.0031 mol). The reaction was stirred at 25° C. for 16 h, then poured into ethyl acetate (100 ml) and H2O (30 ml). The organic layer was collected, washed with H2O (3×30 ml), dried over MgSO4 and evaporated with 1-5% MeOH/CH2Cl2 to obtain the title compound as a colourless oil. 1H NMR 1.23-1.33 (6H, m), 1.66 (5H, m), 2.04 (1H, br m), 2.72 (2H, t, J=3 Hz), 2.96 (1H, bm), 3.69 (3H, s), 3.98 (1H, br s), 7.11 (1H, d, J=1 Hz), 7.14 (1H, d, J=2 Hz), 7.33 (3H, m), 7.43-7.48 (2H, m), 7.50 (1H, d, J=3 Hz), 7.51 (1H, d, J=1 Hz), 8.07 (br s, indole (NH)), 8.45 (2H, s, Ar (triazole)).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:16][OH:17]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][OH:17])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a stirred solution of 4-bromobenzaldehyde (3.0 g, 16.2 mmol) in ethanol (100 mL) and water (25 mL) was added sodium acetate (1.7 g, 21.0 mmol) and hydroxylamine hydrochloride (1.4 g, 19.5 mmol). The resulting mixture was heated to reflux for 2 hours. The solution was allowed to cool to room temperature, concentrated, and filtered to give 4-bromobenzaldehyde oxime (3.02 g, 93%). 4-Bromobenzaldehyde oxime (0.25 g, 1.25 mmol) was added to a stirred solution of 3-cyanophenyl boronic acid (0.28 g, 1.87 mmol) in glyme (13 mL). Sodium carbonate (0.39 g, 3.75 mmol) in water (2 mL) and tetrakis(triphenylphosphine) palladium (0) (0.07 g, 0.06 mmol) was added and the resulting solution was heated to reflux for 3 hours. The solution was cooled to room temperature and partitioned between a saturated ammonium chloride solution (100 mL) and ethyl acetate (150 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 4′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-3-carbonitrile as a white solid (0.17 g, 61%). MS m/z 223; HRMS: calcd for C14H10N2O+H+, 223.08659; found (ESI, [M+H]+), 223.087; Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.49; H, 4.98; N, 12.51.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:34][C:30]([CH2:35]O)([CH2:31][CH2:32][CH2:33]1)[CH2:29][CH2:28][CH2:27]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:26]12[CH2:34][C:30]([CH2:35][O:7][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=3[O:12][CH3:13])([CH2:31][CH2:32][CH2:33]1)[CH2:29][CH2:28][CH2:27]2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: OCC12CCCN(CCC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(N)c(Cl)cc1C(=O)OCC12CCCN(CCC1)C2
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.02 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol), stirred for one hour, then degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The above prepared suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo and recrystallized from acetonitrile (2 crops) to afford 1.94 g (57%) of pale yellow solid; mp 152.5°-154.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[F:24][C:25]([F:33])([F:32])[C:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([C:26]3([C:25]([F:33])([F:32])[F:24])[CH2:28][CH2:27]3)=[O:30])=[C:16]2[N:15]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), 1-(trifluoromethyl)cyclopropanecarboxylic acid (15 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 72% acetonitrile/water to yield the final product as a beige solid (23 mg, 63% yield). MS (apci) m/z=452.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]#[CH:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu]I>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]1[N:38]=[N:37][N:36]([CH2:35][CH2:34][O:33][S:30]([CH3:29])(=[O:32])=[O:31])[CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCOS(C)(=O)=O)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-prop-2-yn-1-yl-L-glutamate (60 mg, 151 μmol) and 2-azidoethyl methanesulfonate (37.4 mg, 226 μmol) were dissolved in tetrahydrofuran (4 ml). To the solution, copper(I) iodide (2.9 mg, 15 μmol) and N,N-diisopropylethylamine (32 μl, 181 μmol) were added and the mixture was stirred for 18 h at room temperature. The mixture was then concentrated in vacuo and the residue was purified by preparative reversed phase HPLC. The product fractions were collected, lyophilized, and purified again by silicagel chromatography to yield 50 mg (47%) of the product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]([CH3:40])=[N:38][N:39]=2)=[C:31]([CH3:41])[CH:30]=1>>[CH3:19][C:20]1[CH:25]=[C:24]([C:26]([N:15]2[C:16]3[CH:17]=[C:18]4[C:5]5([CH2:8][O:9][C:10]4=[CH:11][C:12]=3[CH2:13][CH2:14]2)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[O:27])[CH:23]=[CH:22][C:21]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]([CH3:40])=[N:38][N:39]=2)=[C:31]([CH3:41])[CH:30]=1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3C)cc2C)o1
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3C)cc2C)o1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 2,3'-dimethyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D36) using a similar procedure to Example 1 (31%). This was converted to its oxalate salt and crystallised from acetone/methanol as a pale yelloe solid mp. 193-195° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9](=[O:18])[C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[O:17][N:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:18])[C:3]=2[CH:4]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1cc(I)ccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc2ccc(I)cc2c1=O
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A solution of ethyl 3-(2-fluoro-5-iodophenyl)-2-(hydroxyimino)-3-oxopropanoate (Preparation 16, 1.3 g) in toluene (20 mL) is heated to reflux under nitrogen for 48 h. The reaction mixture is cooled to room temperature and concentrated in vacuo to give 1.33 g of a crude yellow solid which is recrystallized from ether to afford 0.65 g of the title compound as a yellow crystalline solid. Physical characteristics: mp 130-131: 1H NMR (300 MHz, CDCl3) δ1.45, 4.51, 7.35, 8.09, 8.50; IR (drift) 2475, 2425, 2382, 2350, 2260, 1742, 1663, 1456, 1332, 1240, 1195, 1150, 1010, 987, 831 cm−1; HRMS (FAB) m/z 345.9581 (C11H8INO4+H). Anal. Found: C, 38.03; H, 2.52; N, 4.06.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([CH2:17][NH2:18])[OH:16]>C(#N)C>[CH2:7]1[C:3]2([CH2:6][CH2:5][CH2:4]2)[CH2:2][N:18]1[CH2:17][CH2:15][OH:16]
Reactant: BrCC1(CBr)CCC1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CC2(CCC2)C1

Procedure:
To a three neck 3 L round bottom flask was added 1,1-bis(bromomethyl)cyclobutane (100 g, 0.43 mol), potassium carbonate (285 g, 2.06 mol), acetonitrile (1000 mL) and ethanolamine (37.8 g, 0.62 mol). The reaction mixture was heated to reflux for 2 days. The reaction mixture was concentrated to half volume and water was added (300 mL). The aqueous layer was extracted with dichloromethane (2×500 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([Cl:17])=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[Br:20].B(O)(O)[OH:22].S(=O)(=O)(O)O.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(Br)=CC=1Br>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([Cl:17])=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([OH:22])=[CH:4][C:3]=1[Br:20]
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccc(Cl)cc1C2=O
Reactant: OB(O)O
Agent: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1ccc(Cl)cc1C2=O

Procedure:
When 104 g of 1-amino-2,4-dibromo-6-chloroanthraquinone (preparation see Example 467a) are treated with boric acid/sulphuric acid according to the procedure for 1-amino-2,4-dibromoanthraquinone in BIOS 1484, page 5, then 83.9 g, corresponding to 95% of theory, of 1-amino-2-bromo-4-hydroxy-6-chloroanthraquinone are obtained.
Reaction SMILES: [F:1][C:2]([F:36])([CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[CH2:18][O:17][N:16]=2)=[C:11]([CH3:34])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClC(=O)C(OC)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[F:36][C:2]([F:1])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:28])[CH3:29])=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=3)[CH2:18][O:17][N:16]=2)=[C:11]([CH3:34])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccc(C2=NOCN2c2ccc(OC(C)C)c(C(F)(F)F)c2)c(C)c1
Agent: CN(C)c1ccncc1
Agent: COC(=O)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)Cc1ccc(C2=NOCN2c2ccc(OC(C)C)c(C(F)(F)F)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 29 mg (0.06 mmol) of ethyl 2,2-difluoro-3-hydroxy-3-(4-(4-(4-(isopropoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from EXAMPLE 75, Step D) and 21 mg (0.17 mmol) of 4-dimethylaminopyridine in 5.0 mL of CH2Cl2 at ° C. was added 10 μL (0.11 mmol) of methyl chlorooxoacetate. After stirring at 0° C. for 10 min and rt for 20 min, the reaction mixture was diluted with 20 mL of EtOAc and washed with diluted HCl (10 mL), saturated NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over MgSO4 and concentrated to give the crude ester product.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[C:27]([NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[O:28])=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+]>CC(C)=O>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:16][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[C:27]([NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[O:28])=[CH:10][CH:11]=1
Reactant: CC(=O)OCc1ccc(-c2[nH]c(-c3cccc4ccccc34)nc2C(=O)Nc2nccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1nccs1)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
5-(4-Acetoxymethylphenyl)-2-(1-naphthyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (2.98 g) obtained in Example 60(2) was dissolved in acetone (250 ml) and 0.25 M aqueous sodium hydroxide solution (56 ml) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr. Acetone was evaporated under reduced pressure and the residue was acidified with aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate to give 5-(4-hydroxymethylphenyl)-2-(1-naphthyl)-N-(2-thiazolyl)imidazole-4-carboxamide (2.08 g), melting point 226-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][NH:22][CH3:23]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:22]([CH3:23])[CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CNC
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN(C)C(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and dimethylamine (4.5 mg, 0.12 mmol). The title compound was obtained as a solid (5.8 mg, 16.0% yield). MS m/z: 378.90, 380.80 [M+H]+.
Reaction SMILES: N1C2C(=CC=CC=2)C(C(=O)C)=CC=1.[CH3:14][N:15]1[C:23]2[C:18](=[C:19]([CH:24]([OH:26])[CH3:25])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>[O-2].[Mn+2].ClCCl>[CH3:14][N:15]1[C:23]2[C:18](=[C:19]([C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: CC(O)c1cccc2c1ccn2C
Agent: [Mn+2]
Agent: CC(=O)c1ccnc2ccccc12
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1cccc2c1ccn2C

Procedure:
The title compound was prepared by the same procedure for 1-quinolin-4-yl-ethanone from 1-(1-Methyl-1H-indol-4-yl)-ethanol (3.0 g, 17 mmol), manganese oxide (8.69 g, 100 mmol, Aldrich) and dichloromethane (50 mL). The crude title compound was obtained in form as yellow oil in 98% yield (2.9 g, 16.7 mmol).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:50]([OH:52])=O)[CH:16]=[C:17]2[C:21]=1[N:20]([CH2:22][CH2:23][CH2:24][NH:25][C:26]1[N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:28]=[CH:29][N:30]=1)[N:19]=[CH:18]2)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:86][CH2:87][C@H:88]([NH:93][S:94]([C:97]1[C:102]([CH3:103])=[CH:101][C:100]([CH3:104])=[CH:99][C:98]=1[CH3:105])(=[O:96])=[O:95])[C:89]([O:91]C)=[O:90].[Li+].[OH-]>C1COCC1>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:50]([NH:86][CH2:87][C@H:88]([NH:93][S:94]([C:97]2[C:102]([CH3:103])=[CH:101][C:100]([CH3:104])=[CH:99][C:98]=2[CH3:105])(=[O:96])=[O:95])[C:89]([OH:91])=[O:90])=[O:52])[CH:16]=[C:17]2[C:21]=1[N:20]([CH2:22][CH2:23][CH2:24][NH:25][C:26]1[NH:30][CH:29]=[CH:28][N:27]=1)[N:19]=[CH:18]2
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(C(=O)O)cc2cnn(CCCNc3nccn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reactant: COC(=O)[C@H](CN)NS(=O)(=O)c1c(C)cc(C)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N[C@@H](CNC(=O)c2cc(OCCCN)c3c(cnn3CCCNc3ncc[nH]3)c2)C(=O)O)c(C)c1
Reaction time: 0.17 h

Procedure:
A solution of 7-(3-[(tert-butoxy)carbonylamino]-propoxy}-1-(3-([1-(triphenylmethyl)imidazol-2-yl]amino)propyl)-1H-indazole-5-carboxylic acid is treated with Hunig's base and HBTU, then is stirred for about 10 min. The reaction mixture is treated with methyl 3-amino-2(S)-(2,4,6-trimethyl-benzenesulfonyl)aminopropionate. The product is then isolated via chromatography. The methyl ester is saponified using LiOH in THF, and the trityl and boc protecting groups are removed by treatment with trifluoroacetic acid to give the title compound. It is purified by reversed phase preparative HPLC.