Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[CH:3][CH:2]=1.[C:9]([OH:18])(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12].O>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[OH:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[C:9]([O:18][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:17]
Reactant: O=C(O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=C(OCc1ccccc1)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
BnBr (1.75 mL, 14.631 mmol) was added to a solution of salicylic acid (2.0 g, 14.625 mmol) in TBAF (17.5 mL, 1 M solution in THF) and the reaction mixture was stirred at r.t. overnight (16 h). The organic layer was poured into H2O (100 mL) and extracted with EtOAc (70 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (2% EtOAc/hexanes) to furnish 2.53 g of benzyl 2-hydroxybenzoate (colourless oil, yield: 76%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:6]=2[N:7]=1.[OH-:23].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:6]=2[N:7]=1
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Reactant: [OH-]
Agent: [Na+]
Product: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c12

Procedure:
A mixture of the compound from Step B (104 mg, 0.32 mmol) in 2N aqueous NaOH (10 mL) was stirred at reflux temperature for 15 min. The solution was cooled in ice bath, neutralized with 2 N aqueous HC1, and evaporated to dryness. The residue was suspended in MeOH, mixed with silica gel, and evaporated. The solid residue was placed onto a silica gel column (packed in a solvent mixture of CH2Cl2/MeOH: 10/1) which was eluted with a solvent system of CH2Cl2/MeOH: 10/1 and 5/1. The fractions containing the product were collected and evaporated to dryness to yield the title compound (48 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH:8]([OH:27])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:26])[CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:20][C:15]=2[CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[CH3:33][N:34]([CH:36](OC)OC)[CH3:35].C1(C)C(C)=CC=CC=1>CO>[CH3:33][N:34]([CH3:36])[CH:35]=[CH:2][C:1]([C:4]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH:8]([OH:27])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:26])[CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:20][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(C)=O)cccc2o1
Solvent: Cc1ccccc1C
Solvent: CO
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(=O)C=CN(C)C)cccc2o1

Procedure:
A mixture of 0.884 parts of ethyl 5-(3-[2-acetyl-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate and 0.235 parts of N,N-dimethylformamidedimethylacetal was stirred in 43 parts of xylene at 120°-130° for 3 hours whilst the methanol produced was removed simultaneously by fractional distillation. Overnight cooling of the resulting solution gave a solid which was collected and crystallised from ethanol to give 0.3362 parts of ethyl 5-(3-[2-{3-dimethylaminoacryloyl}-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate, m.pt. 159°-165°.
Reaction SMILES: C([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2(=[O:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=12)(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[OH:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2(=[O:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=12
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=S1(=O)c2ccccc2Nc2c1cc(O)c1ccccc21
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine-7,7-dioxide (6.6 g) in methanol (200 ml) there was added 2N aqueous sodium hydroxide solution (132 ml) and the mixture was stirred in the absence of air at room temperature for 7 minutes; at that point an amber solution had resulted. There was rapidly added 10% aqueous acetic acid solution (200 ml) causing precipitation of the title compound which was collected by filtration (5.68 g). A sample (500 mg) was crystallized from THF affording purified product (250 mg), m.p. 334° C. (dec).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[S:32])=[CH:26][CH:25]=1)#[N:23]>C(O)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]2[S:32][C:2]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:33]=2)=[CH:28][CH:29]=1)#[N:23]
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: N#Cc1ccc(NC(N)=S)cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2sc(Nc3ccc(C#N)cc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.413, 1.11 mmol) in ethanol (10 mL) in a 25 mL round bottom flask was added N-(4-cyanophenyl)thiourea (0.207 g, 1.17 mmol). The solution was heated to reflux (24 hours) and the reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with sodium carbonate solution (10%, 3×20 mL), brine (1×20 mL), dried over sodium sulfate, filtered and concentrated yielding a solid. This solid was flash chromatographed (1:1, hexane:ethyl acetate with 1% acetic acid). The resulting product was recrystallized from methylene chloride and isooctane yielding 2-(4-cyanophenylamino)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole (0.266 g, 53%) as a pale yellow solid: mp 273°-274° C.; 1HNMR (DMSO d6) 400 mHz 10.98 (s, 1 H), 7.86 (d, J=8.32 Hz, 2 H), 7.83 (d, J=9.05 Hz, 2 H), 7.76 (d, J=8.80 Hz, 2 H), 7.55-7.47 (m, 4 H), 7.21 (t, J=8.80 Hz, 2 H), 3.22 (s, 3 H); MS m/z 450 (M+H). HRMS Δ=2.6 mmu.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17](=O)[CH3:18])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1(O)[CH:26]=CC=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccccc1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)Oc1ccccc1

Procedure:
Alternatively, N-t-Butoxycarbonyl-2-phenoxyglycine n-butyl ester was prepared by heating a mixture of 1.5 g. (0.005 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 0.5 g. (0.005 mol.) of phenol at 150° for one hour. The residue was dissolved in ethyl acetate and the resulting solution was washed with cold 10% aqueous sodium hydroxide, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:5]([NH:6][CH:7]([CH3:11])[C:8](Cl)=[O:9])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.Cl.[CH3:21][NH:22][OH:23].C([O-])(=O)C.[Na+]>C(Cl)Cl.O>[CH3:21][N:22]([C:8](=[O:9])[CH:7]([NH:6][C:5]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=1[N+:17]([O-:19])=[O:18])[CH3:11])[OH:23]
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)Cl)c([N+](=O)[O-])c1
Reactant: CNO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of 2.0 g of 2-(4-methyl-2,6-dinitroanilino)propionyl chloride, prepared as in Example 1, in 50 ml of methylene chloride was added dropwise to a stirred solution of 2.0 g of N-methylhydroxylamine hydrochloride and 6.0 g of sodium acetate in 50 ml of water at 0°-5° C. The mixture was stirred for 2 hours, after which the organic layer was spearated, dried and evaporated to dryness. The yellow residue was recrystallised from benzene to give 3, m.p.: 171°-172° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].O1CCCCC1[O:12][NH:13][C:14]([C@H:16]([C@@H:26]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:27]([NH:29][N:30]([S:39]([CH3:42])(=[O:41])=[O:40])[C:31]1[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([CH3:38])[N:32]=1)=[O:28])[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15]>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[OH:12][NH:13][C:14]([C@H:16]([C@@H:26]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:27]([NH:29][N:30]([S:39]([CH3:42])(=[O:41])=[O:40])[C:31]1[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([CH3:38])[N:32]=1)=[O:28])[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:15]
Reactant: Cc1cc(N(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c2ccccc2)C(=O)NOC2CCCCO2)S(C)(=O)=O)nc(C)n1
Agent: CS(=O)(=O)O
Product: Cc1cc(N(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c2ccccc2)C(=O)NO)S(C)(=O)=O)nc(C)n1

Procedure:
In a manner to that described in the first paragraph of Example 2, but using methanesulphonic acid in place of p-toluenesulphonic acid, starting from 0.049 g of (E)-2(R)-[1(S)-[(tetrahydro-2-(RS)pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-(2,6-dimethyl-4-pyrimidinyl)valerohydrazide there was obtained 0.039 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-(2,6-dimethyl-4-pyrimidinyl)valerohydrazide methanesulphonate in the form of an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.C(N(CC)C(C)C)(C)C.[NH2:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C)C(=O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[C:6]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:7]=1)=[O:21]
Reactant: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCBr
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCNC1CCOCC1
Temperature: 120 °C
Yield: 71.2 %

Procedure:
To a solution of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide (0.050 g, 0.12 mmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) and 4-aminotetrahydropyran (0.032 mL, 0.32 mmol) in a heavy-walled sealed tube. The solution was heated under microwave irradiation at 120° C. for 1 h. The solution was concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown solid (0.039 g, 59%). LCMS m/z (%)=457 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.81 (dd, J=2.6, 9.0 Hz, 1H), 7.79-7.72 (, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.48-7.40 (m, 1H), 7.28-7.20 (m, 2H), 6.34 (d, J=1.8 Hz, 1H), 4.28-4.23 (m, 2H), 3.84 (dd, J=4.0, 11.4 Hz, 2H), 3.69 (s, 3H), 3.40-3.32 (m, 2H), 3.32-3.14 (m, 2H), 3.14-3.03 (m, 1H), 1.85 (m, 2H), 1.48-1.36 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N(C)C)=O)=NC(N(C)C)=O.O[CH2:64][CH2:65][N:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:64][CH2:65][N:66]5[CH2:71][CH2:70][O:69][CH2:68][CH2:67]5)=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Oc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: OCCN1CCOCC1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(OCCN6CCOCC6)ccc5c34)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.1 %

Procedure:
To a solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-ol (50 mg, 0.11 mmol, from Example 34) in THF (2 mL) was added triphenylphosphine (43.5 mg, 0.17 mmol, 1.5 equiv) and 1,1′-Azobis(N,N-dimethylformamide) (28.6 mg, 0.17 mmol, 1.5 equiv) under nitrogen. The reaction mixture was stirred at rt for 5 mins and 4-(2-hydroxyethyl)morpholine (21.8 mg, 0.17 mmol, 1.5 equiv) was then. The reaction mixture was stirred at rt for 15 h and it was concentrated in vacuo. The crude material was purified by preparative HPLC to give N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-(2-morpholin-4-ylethoxy)[1]benzothieno[2,3-d]pyrimidin-4-amine as a white solid (18.1 mg, 29%). 1H-NMR (DMSO-d6) δ 8.08 (broad s, NH), 7.65 (s, 1H), 7.62 (d, J=9.2 Hz, 1H), 6.91 (m, 2H), 6.74 (m, 3H), 6.63 (m, 1H), 6.48-6.37 (m, 3H), 4.42 (s, 2H), 3.38 (t, 2H), 2.75 (t, 4H), 1.90 (t, 2H), 1.65 (t, 4H), LCMS RT=2.75 min, [M+H]+=565.20.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A83) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3]1([CH3:12])[O:9][CH:8]2[CH:5]([CH2:6][C:7]2([CH3:11])[CH3:10])O1.C[Si](C)(C)[Br:15]>C(Cl)Cl>[Br:15][C@@H:5]1[CH2:6][C:7]([CH3:11])([CH3:10])[C@H:8]1[O:9][C:3](=[O:2])[CH3:12]
Reactant: COC1(C)OC2CC(C)(C)C2O1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](Br)CC1(C)C
Yield: 78.9 %

Procedure:
34.4 g (0.2 mol) of 3-methoxy-3,6,6-trimethyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 33.6 g (0.22 mol) of trimethylbromosilane in 150 ml of methylene chloride are heated to the reflux for 15 hours. Evaporation and fractional distillation of the residue in vacuo give 34.9 g (79%) of trans-1-bromo-2-acetoxy-3,3-dimethyl-cyclobutane. Boiling point14 87°-89°, nD20 1.4629.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:12].[Cl:13]N1C(=O)CCC1=O.[Cl-].[Li+]>CN(C)C=O>[NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:12]
Reactant: Nc1c(F)ccc2c1OCCC2
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Nc1c(F)cc(Cl)c2c1OCCC2
Reaction time: 1.5 h
Yield: 49.6 %

Procedure:
To a stirred solution of 3.7 grams (0.022 mole) of 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran in 50 mL of N,N-dimethylformamide was added dropwise a solution of 3.0 grams (0.022 mole) of N-chlorosuccinimide in about 20 mL of N,N-dimethylformamide. Upon completion of the addition, the reaction mixture was stirred for about 90 minutes and poured into an aqueous 10% lithium chloride solution. The mixture was extracted with diethyl ether. An insoluble material was collected by filtration and dissolved in methylene chloride. The methylene chloride solution was washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was set aside. The diethyl ether extract was washed with an aqueous 10% lithium chloride solution and dried with magnesium sulfate. The mixture was filtered, and the filtrate was combined with the methylene chloride filtrate. The combination was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel with 1:4 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.2 grams of 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)OC(=O)C1CCCn2c(C(=O)c3ccc(F)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc2n1CCCC2C(=O)O

Procedure:
A solution of 180 mg. of isopropyl 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 5 ml. of methanol is treated with a solution of 200 mg. of potassium carbonate in 1.5 ml. of water. The reaction mixture is refluxed under a nitrogen atmosphere for 24 hours, cooled, and evaporated to dryness. The residue is taken up in water and the resultant mixture extracted with ethyl acetate to remove the neutral impurities. The aqueous phase is made acidic with concentrated hydrochloric acid and the product is extracted with ethyl acetate. The extract is washed with sodium chloride, dried over sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from acetone hexane affords 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid (XIa, R=H, L=p-F, n=1), m.p. 164° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:13][CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]=[CH:8]2)#[N:2].[OH-:37].[Na+].OO>CS(C)=O>[F:27][C:26]([F:29])([F:28])[O:25][C:22]1[CH:21]=[CH:20][C:19]([CH:18]2[CH2:17][NH:16][CH2:15][CH:14]2[NH:13][C:6]2[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:12]3[C:7]=2[CH:8]=[N:9][CH:10]=[N:11]3)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc(C#N)c3ncncc23)C(c2ccc(OC(F)(F)F)cc2)C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(NC2CNCC2c2ccc(OC(F)(F)F)cc2)c2cncnc12
Yield: 69.5 %

Procedure:
Tert-butyl 3-(8-Cyano-quinazolin-5-ylamino)-4-(4-trifluoromethoxy-phenyl)-pyrrolidine-1-carboxylate (100.00 mg; 0.20 mmol; 1.00 eq.) was stirred with aqueous 2.0M NaOH (1 ml; 2.00 mmol; 10.00 eq.) and aqueous 35% H2O2 (0.19 ml; 2.00 mmol; 10.00 eq.) in DMSO (8 ml) at 40° C. overnight. The crude was purified by pre-HPLC to yield the title compound (58 mg, 56.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:16]2[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(Cl)cc1
Yield: 50 %

Procedure:
4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.036 g (50%) of 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.Cl.[CH:25]1([C:28]([NH2:31])([CH3:30])[CH3:29])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:25]1([C:28]([NH:31][C:21]([C:18]2[C:16]3=[N:17][C:12]([C:4]4[C:5]5[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=5)[N:2]([CH3:1])[N:3]=4)=[CH:13][N:14]=[C:15]3[NH:20][CH:19]=2)=[O:23])([CH3:30])[CH3:29])[CH2:27][CH2:26]1
Reactant: CC(C)(N)C1CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C5CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and 2-cyclopropylpropan-2-amine hydrochloride (53 mg, 0.39 mmol) in DMF (3 mL), was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours, and then poured into water (5 mL) and filtered. The crude solid was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 58% acetonitrile/42% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 88% acetonitrile/12% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(2-cyclopropylpropan-2-yl)-2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (25 mg, 25%) as a white solid. MS: (M+H)+=389; 1H NMR (300 MHz, DMSO): δ 9.10 (s, 1H), 8.39-8.36 (m, 2H), 7.97 (s, 1H), 7.55 (s, 1H), 7.08 (d, 1H, J=8.1 Hz), Hz), 4.16 (s, 3H), 2.52 (s, 3H), 1.59-1.53 (m, 1H), 1.25 (s, 6H), 0.47-0.43 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].CN([CH:14]=[O:15])C.C([Li])CCC>CCOCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[CH:14]=[O:15]
Reactant: CN(C)C=O
Reactant: Fc1cc(F)c(Br)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(Br)c(F)cc1F
Yield: 61.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 27 for the preparation of I-27a above, 1,5-dibromo-2,4-difluorobenzene (3 g, 11.07 mmol) in dry ether was reacted with DMF (1.05 mL, 14.39 mmol) and n-butyl lithium (6.08 ml, 11.56 mmol to afford the crude product. Purification by column chromatography on silica gel (2% ethyl acetate in hexane) afforded 1.5 g of the product (61% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:12][C:13]([F:20])([CH:17]([F:19])[F:18])[C:14](Cl)=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:8][C:14](=[O:15])[C:13]([F:20])([F:12])[CH:17]([F:19])[F:18])=[N:6][CH:7]=1
Reactant: O=C(Cl)C(F)(F)C(F)F
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Product: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)C(F)F

Procedure:
5-Chloro-3-nitro-2-aminopyridine is reacted with 2,2,3,3-tetrafluoropropionyl chloride to yield 5-chloro-3-nitro-2-(2,2,3,3-tetrafluoropropionamido)pyridine, which when hydrogenated yields 6-chloro-1-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-1H-imidazo-(4,5-b)pyridine. This compound is reacted with trimethylamine to prepare 6-chloro-1-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-1H-imidazo-(4,5-b)pyridine trimethylamine salt.