Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:21])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CO
Reactant: COc1cc(CC(=O)O)ccc1C(F)(F)F
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C(F)(F)F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-methoxy-4-(trifluoromethyl)phenyl)acetic acid (17.0 g, 72.6 mmol) in MeOH (200 mL), thionyl chloride (10 mL, 141 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 h and concentrated under vacuum to afford the title compound (18.8 g). 1H NMR (DMSO-d6): δ 7.49 (s, 1H), 7.40 (d, 1H), 6.96 (d, 1H), 3.87 (s, 3H), 3.68 (s, 3H), 3.64-3.58 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]#[N:29].O>CN(C)C=O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:27][C:28]#[N:29])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: N#CCBr
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 53.5 %

Procedure:
A suspension of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 52 mg, 0.20 mmol), potassium carbonate (43 mg, 0.31 mmol), bromoacetonitrile (15 μL, 0.22 mmol) in anhydrous N,N-dimethylformamide (1 mL) was stirred at 60° C. for 2.5 hours. After cooling to room temperature, water (10 mL) was added thereto and the precipitated solid was filtered off. The obtained solid was dried under reduced pressure to give the target compound (32 mg) as a pale brown solid (Yield 54%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8](F)[CH:7]=1>C(O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:1][CH2:2][CH3:3])[CH:7]=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Sodium ethoxide (21% in ethanol, 8.6 mL, 26 mmol) was added dropwise to a solution of 4-chloro-2-fluoronitrobenzene (3 g, 17.1 mmol) in ethanol (20 mL), and once addition was complete the reaction was stirred for a further hour. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the solution was washed with water (×2), then brine. The solution was dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a solid, 3.45 g.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>ClCCl>[CH3:28][N:29]([CH:31]=[N:23][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:25][CH:24]=1)[CH3:30]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Product: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
A mixture of 4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzamide (1.25 g) from Example 45 and dimethylformamide dimethylacetal (20 ml) was refluxed for 4 hours and the volatiles removed in vacuo to give a solid. The solid was dissolved in dichloromethane and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (1,40 g), m.p. 232-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH3:16]I>CO.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CI
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1

Procedure:
A mixture of 1 g (4 mmol) 2-Chloro-5-sulfino-benzoic acid in 20 ml methanol and 20 ml water was treated with 10N NaOH to pH=9 before adding 1.7 g (12 mmol) methyliodide. The mixture was heated for 48 h to 80° C. with occasional addition of NaOH to maintain pH=9. After removal of all volatiles HCl conc. was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was taken up in methanol and subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 323 mg (34%) of the title compound. MS (m/e): 233.0 (M−H, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](=[C:12]1[CH:17]=[CH:16][NH:15][CH:14]=[CH:13]1)[C:5]2=O.O.[NH2:20][NH2:21]>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:6][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:21][NH:20]1
Reactant: NN
Reactant: O=C1C(=C2C=CNC=C2)C(=O)c2cc(Br)ccc21
Solvent: O
Product: O=c1[nH]nc(Cc2ccncc2)c2cc(Br)ccc12

Procedure:
Under exclusion of air, 4.75 g (15.7 mmol) 5-bromo-2-(1H-pyridin-4-ylidene)indan-1,3-dione and 14 ml hydrazine hydrate are heated for 4 h to 130° C. Cooling, filtering, and washing with ethanol yields title compound A in the mixture with a little 1-oxo-4-[(pyridin-4-yl)-methyl]-6-bromo-1,2-dihydrophthalazine (B). A: HPLC: tRet(Grad5-40)=1 1.5; 1H-NMR (DMSO-d6) 12.76 (HN), 8.46 (d, J=6, 2H), 8.34 (d, J=2, 1H), 8.07 (dd, J=8, 2, 1H), 7.85 (d, J=8, 1H), 7.30 (d, J=6, 2H), 4.33 (s, 2H); B: HPLC: tRet(Grad5-40)=1 1.3; 1H-NMR (DMSO-d6) 12.76 (HN), 8.46 (d, J=6, 2H), 8.16 (d, J=8, 1H), 8.14 (d, J=2, 11H), 8.00 (dd, J=8, 2, 1H), 7.3 (d, J=6, 2H), 4.35 (s, 2H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC3(CC2)OCCO3)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC(=O)CC2)c1

Procedure:
A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carbomethoxyphenylethynyl)cyclohexane (0.060 g, 0.12 mmol) in tetrahydrofuran (5 mL) containing 3N hydrochloric acid (0.60 mL) under an argon atmosphere was heated at 55°-60° C. for 2 h. The cooled reaction mixture was partitioned between ice cold dilute aqueous sodium carbonate solution and ethyl acetate. The organic phase was washed with water, saturated brine, was dried over sodium sulfate, and was concentrated in vacuo. The residue was chromatographed (silica gel), eluting with 15% ethyl acetate/hexanes, to afford a resin. Anal. (C28H30O5.1/4 H2O) calcd: C 74.56, H 6.82, found: C 74.43, H 6.80. 1H-NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.00 (d-d, J=1.5 Hz;J=6.6 Hz, 1H), 7.65 (d-d, J=1.3 Hz, J=7.7 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.21 (d, J=2.1, 1H), 7.12 (d-d, J=2.0 Hz, J=8.5 Hz, 1H), 6.87 (d, J=8.5 Hz,1H), 4.81 (m, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.04 (d-t, J=6.0 Hz, J=14.2, 2H), 2.50 (d,br, J=14.8, 2H), 2.4-2.2 (m, 4H), 2.0-1.5 (m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([NH:16][CH2:17][CH2:18]Br)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[C:12]([O:11][C:9](=[O:10])[NH:16][CH2:17][CH2:18][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C

Procedure:
A flask was charged with 4-nitro-1H-pyrazole (3.5 g, 30.02 mmol), 2-(boc-amino)ethylbromide (6.9 g, 30.02 mmol), Cs2CO3 (1.07 g, 33.02 mmol) and MeCN (60 mL). The resulting reaction mixture was stirred at reflux (80° C.) for 1.5 h, then allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM. The filtrate was concentrated to yield tert-butyl(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate as a light orange oil, which was used in the next step without further purification. LC-MS conditions B: tR=0.63 min, [M+H]+=257.35.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[N:12]([Sn](C)(C)C)=[N+:13]=[N-:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]1[N:12]=[N:13][NH:14][N:5]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1c(F)cc(Cl)cc1Br
Solvent: Cc1ccccc1
Product: Fc1cc(Cl)cc(Br)c1-c1nn[nH]n1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of 2-bromo-4-chloro-6-fluoro-benzonitrile (4 g, 17.06 mmol) and azidotrimethyltin (3.86 g, 18.77 mmol) in toluene (100 ml) was heated to 120° C. for 72 h. After completion of the reaction, the mixture was partitioned between EtOAc (50 ml) and aqueous 0.5N HCl solution (40 ml). The organic layer was separated, washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure to afford the title compound (4.2 g, 87%) as red solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)[N:34]=1.[CH2:55](O)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)[N:34]=1
Reactant: CCCCCCCCO
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
2.00 g (11.5 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 3.00 g (11.5 mmol) of triphenylphosphine in 50 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 2.42 g (7.7 mmol) of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine and 1.00 g (7.7 mmol) of 1-octanol are then added. After a reaction time of 18 hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 95:5 hexane/ethyl acetate). Recrystallization from acetonitrile gives 1.38 g of 2-fluoro-3-octyloxy-6-(4-octyloxyphenyl)pyridine. ##STR19##
Reaction SMILES: NC(=O)[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]C(C)C.N1CC[CH:42]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:40]1>>[C:45]([CH:42]1[CH2:41][CH2:40][N:8]([C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]2[C:26]3[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=3[C:20]([C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=3[F:36])=[N:19]2)=[O:17])[C:11]([CH3:14])([CH3:12])[CH3:13])[CH2:3][CH2:4]1)(=[O:46])[NH2:47]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Reactant: NC(=O)C1CCNCC1
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)N2CCC(C(N)=O)CC2)C(C)(C)C)C1

Procedure:
Compound 79 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with piperidine-4-carboxamide. LCMS (+ESI) m/z=535.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([O:14]C(=O)C2C=CC=C(Cl)C=2)[CH:13]=1)=[O:6].[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([OH:14])[CH:13]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1OC(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-chlorobenzoyl chloride (32.81 g, 187.5 mmol, Aldrich) in tetrahydrofuran (50 mL) was added to a solution of 5-amino-o-cresol (9.24 g, 75 mmol, Aldrich), triethylamine (31.43 mL, 225 mmol, Aldrich) and tetrahydrofuran (150 mL) dropwise with magnetic stirring and cooling in an ice-water bath. When the addition was complete, the mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was then diluted with water (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL). After stirring for another 30 minutes, precipitate was collected to give crude 3-chloro-benzoic acid 5-(3-chloro-benzoylamino)-2-methyl-phenyl ester as an off-white powder. (Yield 31.74 g). Crude 3-chloro-benzoic acid 5-(3-chloro-benzoylamino)-2-methyl-phenyl ester (11.42 g, 28.5 mmol) was dissolved in a mixture of tetrahydrofuran (70 mL), methanol (140 mL) and aqueous 1N sodium hydroxide (28.5 mL, 28.5 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to remove most of the organic solvent. The resulting suspension was diluted with water (90 mL) and saturated aqueous sodium bicarbonate solution (10 mL). After standing for 30 minutes, precipitate was collected, washed with water and dried to give 3-chloro-N-(3-hydroxy-4-methyl-phenyl)-benzamide as an off white powder. (Yield 6.06 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][N:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[CH2:2][C:3]1=[O:4]
Reactant: CN(C(=O)CCl)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1C(=O)Cc2cc([N+](=O)[O-])ccc21
Temperature: 80 °C

Procedure:
The mixture of 2-Chloro-N-methyl-N-(4-nitrophenyl)acetamide (100 mg, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), 2-(di-tert-butylphosphino)biphenyl (13 mg, 0.044 mmol) and triethylamine (91 μl, 0.66 mmol) in toluene was heated at 80° C. for 3 h. The reaction was 78% complete by NMR.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[C:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])=[C:5]([CH3:28])[N:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33](CO)[CH2:32][CH2:31]1>O1CCOCC1>[NH2:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[C:17]([CH2:23][C:24]([O:26][CH2:27][CH:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:25])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])=[C:5]([CH3:28])[N:4]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1OC
Reactant: CN1CCC(CO)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OCC2CCN(C)CC2)ccc1OC
Temperature: 80 °C

Procedure:
4M HCl in dioxane (1.5 mL) was added to a mixture of the product from step (v) (300 mg) and (1-methylpiperidin-4-yl)methanol (520 mg). The suspension was heated at 80° C. for 24 h and the solvent evaporated under reduced pressure. The residue was purified by RPHPLC to give the title compound as a gum, 10 mg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[C:22](=[O:23])[C:21]3[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:24])=[N:2]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 4.4 %

Procedure:
Compound 2 (0.06 g, 0.25 mmol) was dissolved in xylene (2.0 mL) and the solution was added with phthalic anhydride (83 mg, 0.56 mmol) and triethylamine (89 μL, 0.64 mmol), followed by stirring at 60° C. for 2 hours. Then, the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 159 (4.0 mg, 4%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:11].[O:12](S(C(F)(F)F)(=O)=O)[S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14].CCN(CC)CC>C(Cl)Cl>[F:17][C:16]([F:19])([F:18])[S:13]([O:11][C:3]1[CH:4]=[CH:5][C:6]2=[N:7][O:8][N:9]=[C:10]2[C:2]=1[CH3:1])(=[O:14])=[O:12]
Reactant: Cc1c(O)ccc2nonc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2nonc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methyl-2,1,3-benzoxadiazol-5-ol (2.10 g, 17.9 mmol) in 40 mL of dry DCM was added Tf2O (7.61 g, 26.9 mmol) dropwise at −78° C. under Ar and stirred for 5 minutes, then Et3N (2.73 g, 26.9 mmol) was added dropwise to the mixture and the reaction was stirred at 0° C. for 4 hours. Then the reaction was poured into 200 mL of ice water and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried and concentrated, the residue was purified by silica gel column to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:14])([F:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([F:13])([F:14])[CH2:11][O:12][S:16]([CH3:15])(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(F)(F)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
A solution of 3-benzyloxy-2,2-difluoropropan-1-ol (Compound 59H, 202 mg, 1 mmol) and methanesulfonyl chloride in DCM (3 mL) was cooled to 0° C. and treated with Et3N (0.28 mL, 2 mmol). The reaction mixture was allowed to warm at RT. After 12 h, the reaction mixture was diluted with DCM (5 mL) and washed with aq. K2CO3 (4×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 220 mg (82%) of the title compound as yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.33 (m, 5H), 4.62 (s, 2H), 4.47 (t, J=12.4 Hz, 2H), 3.74 (t, J=12.4 Hz, 2H), 3.05 (s, 3H).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:10]=[CH:11][C:12]=1[CH2:13]Br)(C)(C)C.[C-:26]#[N:27].[Na+]>CN(C=O)C.CCOC(C)=O>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:26]#[N:27])=[C:7]([OH:6])[CH:8]=1
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The mixture of 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-bromomethylphenyl)-1,3-benzoxazole (1.6 g, 3.8 mmol) and sodium cyanide (560 mg, 11.4 mmol) in DMF (10 mL) was stirred at 90° C. overnight. After cooling to rt, the mixture was diluted with EtOAc (100 mL), washed with H2O (2×50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford the desired [4-(1,3-benzoxazol-2-yl)-2-hydroxyphenyl]acetonitrile as yellow solid. 1H NMR(CD3OD, 300 MHz), δ10.6(s, 1H), 7.8(m, 2H), 7.7(m, 2H), 7.5(d, 1H), 7.4(m, 2H). MS (ESI) 251 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(O[CH2:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOCC(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CCOC(=O)C(=CNc1cccc(C(F)(F)F)c1)C(=O)OCC
Temperature: 100 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 3-(trifluoromethyl)aniline (40 mL, 0.32 mmol) and diethyl ethoxymethylmalonate was heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to room temperature at which time the solution solidified to provide 102 g of diethyl 2-{[3-(trifluoromethyl)anilino]methylene}malonate as a cream colored solid.