Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]2[C:7]([O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Br:23]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C1COCC1>[Br:23][C:10]1[C:5]2[O:4][CH2:3][C:2]([CH3:1])([CH3:22])[C:6]=2[C:7]([O:11][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])=[CH:8][CH:9]=1
Reactant: CC(C)[Si](Oc1cccc2c1C(C)(C)CO2)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(Br)c2c1C(C)(C)CO2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane (Intermediate 181, 7.4 g, 23.19 mmol) was dissolved in THF (70.0 mL). N-Bromosuccinimide (4.2 g, 23.88 mmol) was added dissolving in few minutes. This mixture was stirred at room temperature for 3 hrs. More NBS (0.64 g, 3.48 mmol) was added and the reaction mixture was stirred at room temperature for a further hour. CCl4 (50 mL) was added to the reaction mixture and the solution was evaporated to dryness. The residue was re-suspended in CCl4 and stirred at room temperature for 15 min. The white solid was removed by filtration and the wet cake was washed with more CCl4. The CCl4 was swapped with ethyl acetate and the organic solution was washed three times with 2.5% w/w aqueous NaHCO3 and finally with water. The organic solution was dried on anhydrous Na2SO4 and evaporated to dryness to give the title compound (8.6 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH2:8])=[CH:5][N:6]=1.CS[C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:11]([NH:12][N+:13]([O-:15])=[O:14])=[NH:16])=[CH:5][N:6]=1
Reactant: NCc1cnc(Cl)s1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CCO
Product: N=C(NCc1cnc(Cl)s1)N[N+](=O)[O-]
Yield: 77.7 %

Procedure:
A mixture of 0.35 g of 2-chloro-5-thiazolemethanamine, 0.31 g of S-methyl-N-nitroisothiourea and 3 ml of ethanol was heated under reflux for 6 hours. After cooling, the separated crystals were collected by filtration, washed with a small amount of ethanol, and then recrystalized from ethanol to obtain 0.42 g of the title compound as crystals. This compound is No. 9 in Table 1. m.p.: 160.0°-162.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:33]1[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(F)ccc4nc3OC)CC2)c1
Yield: 72 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 72%). MS(ESI) m/z 442 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1.[I:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([N:20]3[CH:21]=[C:17]([I:16])[N:18]=[CH:19]3)[N:3]=2)=[CH:10][CH:11]=1
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(Br)nc(-c2ccc(Cl)cc2)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1

Procedure:
The title compound was prepared from 2-bromo-6-(4-chloro-phenyl)-4-methyl-pyridine (example A.22) (0.94 g, 3.0 mmol) and commercially available 4-iodo-imidazole (0.71 g, 3.3 mmol) according to the general procedure IVa. Obtained as a yellow gum (0.213 g, 18%). MS (ISP) 396.0 [(M+H)+].
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([NH2:8])=[N:4]1)[CH3:2].N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([O:21][C:22](=[O:23])[NH:8][C:5]2[N:6]=[N:7][N:3]([CH2:1][CH3:2])[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCn1nnc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCn1nnc(NC(=O)Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-ethyl-2H-tetrazol-5-ylamine (0.1 g, 0.88 mmol) in dry THF (2 ml) is treated with pyridine (0.09 ml, 1.10 mmol) followed by a solution of phenylchloroformate (0.11 ml, 0.911 mmol) in THF (1 ml). The reaction mixture is stirred at ambient temperature for 1.5 hours, then partitioned between ethylacetate and water. The ethylacetate phase is dried over magnesium sulphate and evaporated to afford (2-Ethyl-2H-tetrazol-5-yl)-carbamic acid phenyl ester as a white solid. 1H NMR (CDCl3, 400 MHz) δ, 7.90 (1H, brs), 7.30 (2H, m), 7.15, (3H, m), 4.60 (2H, q) 1.60 (3H, t).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[CH:61]=[CH:62][C:63]2[S:67][C:66]([CH2:68]O)=[CH:65][C:64]=2[CH:70]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:68][C:66]2[S:67][C:63]3[CH:62]=[CH:61][C:60]([CH3:59])=[CH:70][C:64]=3[CH:65]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccc2sc(CO)cc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cc3cc(C)ccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (5-methyl-1-benzothien-2-yl)methanol (0.75 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 44%).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1N=NC=CC=1)[CH2:4][CH2:3]2.Br[C:50]1[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][N:51]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:50]1[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][N:51]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(S(C)(=O)=O)cn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 11.9 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridazin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromo-5-(methylsulfonyl)pyridine (0.024 g, 0.100 mmol) was used in place of 3-chloropyridazine. Purification of the crude Step 2 mixture by reverse phase preparative HPLC using Prep HPLC Method 10 gave the title compound as an off-white solid (10.6 mg, 11.9% yield over 2 steps) bis TFA salt. LCMS: m/e 728.5 (M+H)+, 2.22 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.61 (d, J=1.8 Hz, 1H), 7.95-7.87 (m, 3H), 7.19 (d, J=8.2 Hz, 2H), 6.80 (d, J=8.9 Hz, 1H), 5.29 (d, J=4.6 Hz, 1H), 4.90 (s, 1H), 4.82 (br. s., 1H), 3.96-3.85 (m, 1H), 3.85-3.71 (m, 1H), 3.42 (br. s., 1H), 3.37 (s, 3H), 3.27-3.18 (m, 1H), 3.10 (s, 3H), 2.70 (br. s., 1H), 2.14 (dd, J=17.2, 6.3 Hz, 1H), 2.10-1.95 (m, 5H), 1.91-1.77 (m, 3H), 1.74 (s, 3H), 1.71 (d, J=17.4 Hz, 2H), 1.65-1.47 (m, 6H), 1.47-1.34 (m, 3H), 1.34-1.11 (m, 6H), 1.06 (s, 3H), 1.00 (s, 3H), 0.94 (s, 6H), 0.93 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>CN(C=O)C.O>[CH3:16][C:11]1[N:12]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=2)[C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[C:10]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)N(Cc2cccc(OC)c2)C(=O)CC1c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
The product from Example 5, Step 1 (0.627 g, 2.00 mmol, 1.00 equiv) and cesium carbonate (0.975 g, 3.00 mmol, 1.50 equiv) were combined in DMF (9 mL) for 15 minutes at rt. 3-Methoxybenzyl bromide (0.436 mL, 3.12 mmol, 1.56 equiv) was added and the reaction was heated to 100° C. for 6 hours. The reaction was diluted with H2O and extracted with Et2O. The organic phase was washed with H2O and satd. NaCl, dried over MgSO4 and concentrated en vacuo to provide 0.762 mg (88%) of the title compound as an oil. MS (ES+) m/e 434 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[OH-].[Na+].[CH3:13]OS([O-])(=O)=O.C([S+](C)C)CCCCCCCCCCC.C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]1[O:7][CH2:13]1
Reactant: COS(=O)(=O)[O-]
Reactant: COc1cccc(C=O)c1
Agent: CCCCCCCCCCCC[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C2CO2)c1

Procedure:
A mixture of 3-methoxybenzaldehyde (13.4 g, 0.098 mol), a solution of sodium hydroxide (200 g) in water (200 ml), dodecyl-dimethylsulfonium methyl sulfate (51 g, 0.15 mol) and toluene (150 ml) is stirred for 17 hours. Ice is then added and the organic phase is separated, washed with water (3×50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The above product is recovered from the thus obtained residue by distillation at 135°-140° C. and 30 mmHg.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:11]([N:15]=[C:16]=[S:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C.C(OCC)(=O)C>[C:11]([NH:15][C:16]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=S)N[C@@H](CO)c1ccccc1

Procedure:
N-(tert-Butyl)-N′-[(1R)-2-hydroxy-1-phenylethyllthiourea: The process is performed under the conditions of Example 1, starting with 2.74 g of (R)-(−)-2-amino-2-phenylethanol and 2.8 cm3 of tert-butyl isothiocyanate in 15 cm3 of ethanol for 20 hours at a temperature in the region of 20° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. A yellow oil is obtained, which is dissolved in 100 cm3 of ethyl acetate and the organic solution is then washed with twice 50 cm3 of aqueous sodium hydrogen carbonate solution and twice with aqueous sodium chloride solution. After drying over sodium sulfate, the organic solution is filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 4.9 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-phenylethyl]thiourea are obtained in the form of a yellow solid melting at 98° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18](=[O:20])[CH3:19])=O)C1C=CC=CC=1.[N:21]1[C:30]2[C:25](=[N:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.N1CCCCC1>CC(O)C>[N:26]1[C:25]2[C:30](=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:28][C:27]=1[CH:31]=[C:15]1[NH:11][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[N:13][C:14]1=[O:16]
Reactant: CC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C

Procedure:
To a mixture of 2-acetylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (47.1 mg, 0.17 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration to give N-(5-[1, 5]-naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-acetamide as a yellow solid, 15.3 mg (31.8%). HR-ES (+) m/e calcd. for C14H11N5O2: (M+H)+ 282.0986. Found: 282.0985.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][CH3:32])[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 73.2 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-methoxyphenylboronic acid (28 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.024 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a beige solid (39 mg, 73%). LC-MS m/e 437.29 (M+H+)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].CN([CH:24]=[O:25])C>C1COCC1>[Cl:13][C:14]1[C:15]([F:20])=[CH:16][N:17]=[CH:18][C:19]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Fc1cnccc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cncc(F)c1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
To a solution of diisopropylamine (6.4 mL, 45.6 mmol) in THF (50 mL) at −30° C. was added n-butyllithium (2.5 M in hexanes, 18.2 mL, 45.6 mmol) over 15 minutes and the resulting mixture stirred for 15 minutes then cooled to −78° C. A solution of 4-chloro-3-fluoro-pyridine (5.0 g, 38.0 mmol) in THF (10 mL) was added dropwise over 15 minutes then the resulting mixture was stirred at −78° C. for 18 hours. DMF (3.5 mL, 45.6 mmol) was added and the reaction was warmed to room temperature. The mixture was quenched with ammonium chloride (sat. aq., 300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in cyclohexane) to afford the title compound as a pale orange solid (5.1 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 10.47 (s, 1H), 8.88 (s, 1H), 8.70 (s, 1H).
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])[N:31]=[C:30]([C:41]([C:47]([F:50])([F:49])[F:48])([C:43]([F:46])([F:45])[F:44])[OH:42])[CH2:29]3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])C)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:32]1[CH:28]([C:25]2[CH:26]=[CH:27][C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH2:12][CH2:11][CH2:10][NH:8][CH3:1])(=[O:14])=[O:15])[CH:17]=3)=[CH:23][CH:24]=2)[CH2:29][C:30]([C:41]([C:47]([F:48])([F:49])[F:50])([C:43]([F:46])([F:45])[F:44])[OH:42])=[N:31]1
Reactant: CN(CCCS(=O)(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCS(=O)(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.7 %

Procedure:
To 5-{3′-[3-(N-BOC-N-methyl-amino)-propane-1-sulfonyl]-biphenyl-4-yl}-1-(2,4-difluoro-phenyl)-3-(di-(trifluoromethyl)-hydroxy-methyl)-4,5-dihydro-1H-pyrazole (23.0 mg, 0.03 mmol) prepared in Example 395, were added dichloromethane (0.5 mL) and trifluoroacetic acid (24.0 uL, 0.31 mmol). The reaction mixture was stirred at room temperature for 72 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 15.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:15][CH2:16][CH3:17])[CH:3]=1.[OH-].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:15][CH2:16][CH3:17])[CH:3]=1
Reactant: CCOc1cc(N)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Yield: 66.6 %

Procedure:
A mixture of 4.8 parts of methyl 4-amino-2-ethoxy-5-nitrobenzoate, 1.6 parts of sodium hydroxide and 30 parts of water was stirred and refluxed for 30 minutes. The reaction mixture was cooled and 50 parts of water were added. The whole was neutralized by the dropwise addition of glacial acetic acid. The precipitated product was filtered off and crystallized from 2-propanol at 0° C. The product was filtered off, washed with a small amount of 2,2'-oxybispropane and dried, yielding 3 parts (66.6%) of 4-amino-2-ethoxy-5-nitrobenzoic acid; mp. 230° C. (intermediate 34).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1.CCCCCC>CCOC(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Brc1cccc(-c2ccncc2)c1

Procedure:
Prepared according to the general procedure Coupling-1 using 4-pyridinylboronic acid and 1,3-dibromobenzene. Flash chromatography (Hexane:EtOAc, 70:30) afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5])[CH3:2].[CH3:20][O:21]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:20]=[O:21])[CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:18])[CH3:19])=[O:5])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A stirred, cooled (ice bath) solution of of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 36, 0.5 g, 1.92 mmol) in anhydrous dichloromethane (10 mL) was treated with titanium tetrachloride (0.4 mL, 3.26 mmol) followed by α,α-dichloromethyl ether (0.17 mL, 1.92 mmol). The reaction was allowed to warm to ambient temperature over 2 days, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography to afford the title compound (0.11 g, 20%).
Reaction SMILES: C([O:5][C:6](=[O:39])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:37]([NH:36][C:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:18]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:39])=[O:5])[S:12][CH:13]=2)=[CH:33][CH:32]=1)=[O:35])[CH3:38]
Reactant: CCNC(=O)c1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)c1ccc(CN(CCc2csc(SC(C)(C)C(=O)O)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
2-[(4-{2-[{4-[(Ethylamino)carbonyl]benzyl}(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (268 mg) synthesized in Example 437-3 was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (159 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[C:15]([O:19][C:20](=[O:23])[CH2:21][NH2:22])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1ccc(C(=O)NCC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
(4-Methylamino-3-nitro-benzoylamino)-acetic acid tert-butyl ester (1.2 g) was prepared starting from 4-methylamino-3-nitro-benzoyl chloride (1 g), amino-acetic acid tert-butyl ester (721 mg), triethylamine (1.4 mL) in DCM (10 mL). The reaction was stirred at 0° C. for 1 h. The reaction was added to DCM (50 mL) and saturated sodium bicarbonate solution (50 mL). The phases were separated, and the aqueous phase was extracted twice with DCM. The combined organics were dried over sodium sulfate and then filtered. The solvent was evaporated and crude compound was purified by flash chromatography using DCM:methanol gradient.