Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([F:17])=[CH:10][C:5]=1[O:6][CH2:7][C:8]#[N:9])([O-])=O.C(O)(=[O:20])C>[Fe]>[F:17][C:11]1[C:12]([NH2:14])=[CH:13][C:4]2[NH:9][C:8](=[O:20])[CH2:7][O:6][C:5]=2[CH:10]=1
Reactant: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: Nc1cc2c(cc1F)OCC(=O)N2
Yield: 71.7 %

Procedure:
Iron powder (5.6 g) was suspended in 5% acetic acid (112 g), and a solution of 2,4-dinitro-5-fluorophenoxyacetonitrile (2.4 g) in acetic acid (48 g) was dropwise added thereto under reflux, followed by refluxing for an additional 1 hour. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration and washed with a mixture of hexane and ether to give 7-fluoro-6-amino-2H-1,4-benzoxazin-3-(4H)-one (1.3 g; yield, 71.7%).
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].[C:5](OCC)(=[O:13])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>C(#N)C>[OH:13][C:5]1[N:4]=[CH:2][N:3]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=1
Reactant: N=CN
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(O)ncn1
Temperature: 25 °C

Procedure:
Formamidine hydrochloride (2.0 g, 45.4 mmol) and diethyl 2-butynedioate (7.23 mL, 45.4 mmol) were added together in acetonitrile (85 mL) and the resulting mixture was treated dropwise with triethylamine (6.33 mL, 45.4 mmol). The resulting mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, further cooled in an ice bath and the resulting solid was collected by filtration and discarded. The filtrate was evaporated under reduced pressure and the residue purified by column chromatography (Biotage SP4) eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as an off white solid (0.995 g);
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:5][S:6][C:7]=1[N:8]=[CH:9][NH2:10])#[N:2].O(C)[Li]>CO>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:4]2[C:3]3[C:7](=[N:8][CH:9]=[N:10][C:1]=3[NH2:2])[S:6][N:5]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: N#Cc1c(Cc2ccc([N+](=O)[O-])cc2)nsc1N=CN
Agent: [Li]OC
Solvent: CO
Product: Nc1ncnc2snc(Cc3ccc([N+](=O)[O-])cc3)c12
Temperature: 70 °C
Yield: 47.2 %

Procedure:
A solution of Example 338B (0.37 g, 1.29 mmol) in methanol (3 mL) was treated with LiOCH3 (1.4 mL, 1M in methanol), and heated to 70° C. for 4 hours. The reaction was cooled to room temperature resulting in a brown precipitate which was collected by filtration. The filter cake was washed with cold methanol and dried to provide 0.175 g of the desired product. MS (ESI(+)) m/e 288 (M+H)+.
Reaction SMILES: Br[C:2]1[C:23]([S:24]([N:27](CC2C=CC(OC)=CC=2)[C:28]2[S:29][CH:30]=[CH:31][N:32]=2)(=[O:26])=[O:25])=[CH:22][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1.[C:42]([Zn]C#N)#[N:43]>CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Zn]>[C:42]([C:2]1[C:23]([S:24]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)(=[O:26])=[O:25])=[CH:22][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1)#[N:43]
Reactant: N#C[Zn]C#N
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3c(cc2Br)N(c2ccc(C(F)(F)F)cc2OC)CCO3)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Zn]
Solvent: CCOC(C)=O
Product: COc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)c(C#N)cc21
Reaction time: 0.58 h
Yield: 32.2 %

Procedure:
A vial was charged with 6-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (67 mg, 0.100 mmol), dicyanozinc (23.46 mg, 0.200 mmol), bis(tri-t-butylphosphine)palladium(0) (5.11 mg, 9.99 μmol), and zinc (1.960 mg, 0.030 mmol). The vial was flushed with Ar (g), then N,N-dimethylacetamide (500 μl) was added. The vial was sealed and placed in a 60° C. heating bath for 5 h. Additional portions of dicyanozinc (23.46 mg, 0.200 mmol) and bis(tri-t-butylphosphine)palladium(0) (ca. 8.5 mg) were added, and the vial was returned to the heat for 2 h. The mixture was diluted with EtOAc, then washed with water (2×), washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM (1 mL) and TFA (0.5 mL). After 35 min, the mixture was diluted with MeOH and concentrated. The residue was purified by chromatography on 12-g Redi-Sep Gold column (20-70% EtOAc/Heptane, product eluted late) to give ca. 16 mg of a white solid. The material was rechromatographed twice on 12-g Redi-Sep Gold columns, once with 3% MeOH/DCM, then with 0-4% MeOH/DCM to give 6-cyano-4-(2-methoxy-4-(trifluoromethyl)phenyl)-n-(thiazol-2-yl)-3,4-dihydro-2h-benzo[b][1,4]oxazine-7-sulfonamide as a white solid that was about 91% pure by LCMS and NMR: 1H NMR (400 MHz, DMSO-d6) δ=12.91 (br. s., 1 H), 7.56 (d, J=8.1 Hz, 1 H), 7.49-7.40 (m, 2 H), 7.36 (s, 1 H), 7.28 (d, J=4.6 Hz, 1 H), 6.87 (d, J=4.6 Hz, 1 H), 6.60 (s, 1 H), 4.43-4.38 (m, 2 H), 3.87 (s, 3 H), 3.71 (t, J=4.3 Hz, 2 H); m/z (ESI) 497.2 (M+H)+.
Reaction SMILES: [Br-].[F:2][C:3]([F:26])([F:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C@H:41]2[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)#[N:34]>C1COCC1>[F:2][C:3]([F:26])([F:25])[CH2:4][CH:5]=[CH:47][C@H:44]1[CH2:45][CH2:46][C@H:41]([C:38]2[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=2)[CH2:42][CH2:43]1
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](C=CCC(F)(F)F)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3,3,3-trifluoropropyl)triphenylphosphonium bromide (9.0 g, 20.5 millimols) with THF (45 ml) was cooled down to -20° C., followed by adding t-BuOK (2.5 g, 22.5 millimols) to the mixture, stirring for 30 minutes, dropwise adding to the mixture, a THF (50 ml) solution of trans-4-(4-cyanophenyl)cyclohexanecarbaldehyde (4.8 g, 22.5 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the product in the same manner as in Example 1, to obtain raw 4-(trans-4-(4,4,4-trifluorobutenyl)cyclohexyl)benzonitrile (5.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:39])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[CH3:38])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:38][C:31]1[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]=1[C:29](=[O:39])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)NC(C)(C)C)c(C)c1
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Product: COc1ccc(C(=O)NC(C)(C)C)c(CC(=O)[C@@H](Cc2ccccc2F)NC(=O)OC(C)(C)C)c1

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.4 g, 4.29 mmol) and N-tert-Butyl-4-methoxy-2-methyl-benzamide (2.8 g, 13 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [NH2:1][C:2]([CH:9]([CH3:11])[CH3:10])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].C(O)C.OO>O>[NH2:5][C:4]1[S:6][N:1]=[C:2]([CH:9]([CH3:11])[CH3:10])[C:3]=1[C:7]#[N:8]
Reactant: CC(C)C(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Solvent: O
Product: CC(C)c1nsc(N)c1C#N
Temperature: 25 °C
Reaction time: 17.75 h
Yield: 97.2 %

Procedure:
To a stirred mixture of 444.3 g of 3-amino-2-cyano-4-methyl-2-pentenethioamide (from part B) and 1315 ml of ethanol were added dropwise 298 g of 30% hydrogen peroxide (containing 89.4 g of active H2O2) during 1.25 hours. The reaction temperature was maintained at 30°-35° with an ice bath. The reaction mixture was stirred an additional 17.5-18 hours in an ambient temperature water bath. The reaction mixture was poured into 5100 ml of cold water with stirring. The water was cooled in an ice-water bath during addition of the reaction mixture. The mixture was stirred for one hour at 5°-10° and filtered. The filter cake was washed with 2 liters of water and allowed to dry on the suction filter. After air-drying over a weekend, 426.5 g of 5-amino-4-cyano-3-isopropylisothiazole, mp 130°-132° was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:25][C@H:26]([N:28]([CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH2:46][C:47]([F:50])([F:49])[F:48])C(OC(C)(C)C)=O)[CH3:27])=[CH:19][C:20]=2[C:22]([NH2:24])=[O:23])[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:25][C@H:26]([NH:28][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[CH3:27])=[CH:19][C:20]=2[C:22]([NH2:24])=[O:23])[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCCOCc1ccccc1)CC2)N(CCOc1ccccc1OCC(F)(F)F)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCCOCc1ccccc1)CC2)NCCOc1ccccc1OCC(F)(F)F
Yield: 86.6 %

Procedure:
To a solution of (R)-(-)-1-(4-benzyloxybutyl)-5-[2-[N-tert-butoxycarbonyl-2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide (523 mg) in methylene chloride (7.5 ml) was added dropwise trifluoroacetic acid (1.5 ml) with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of chloroform and methanol (10/1) as eluent to give 388 mg of (R)-(-)-1-(4-benzyloxybutyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide melting at 101°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:20][CH:21]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(N)cc2n1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccccc4)nc3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (100 mg, 0.63 mmol) and 6-phenylnicotinic acid (D48) (151 mg, 0.76 mmol) as a cream solid. 1H NMR (400 MHz, DMSO) δ (ppm): 10.75 (s, 1H), 9.25 (d, 1H), 8.50 (s, 1H), 8.45 (dd, 1H), 8.20 (m, 4H), 7.90 (m, 2H), 7.55 (m, 3H), 7.34 (d, 1H), 2.65 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[S:17][C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:22]([C:18]2[S:17][C:16](/[CH:15]=[CH:14]/[C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:20][C:19]=2[CH3:21])=[O:23])[CH2:27][CH2:28]1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)O
Reactant: NC1CCOCC1
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)NC1CCOCC1
Yield: 68 %

Procedure:
As described for example 6f, 2-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (75 mg, 0.22 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (63 mg, 68%) which was obtained as a light yellow solid. MS: m/e=428.3 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])[O:8]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[Na+:27]>O1CCCC1>[C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:8])[O-:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:27]
Reactant: O=P(Oc1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=P([O-])(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 67.8 %

Procedure:
The procedure of Example 1 was followed except that a mixture of phenyl diphenylphosphinate (13.76 g, 46.7 mmol), sodium trimethylsilanolate (5.6 g, 50 mmol), and dry tetrahydrofuran (175 mL) was left standing overnight (as it became impossible to stir). Sodium diphenylphosphinate (7.6 g, 68% yield) was isolated as a white solid: 1H NMR (D2O) δ 6.6-8.0 (m, Ar--H's 10H). Anal. Calcd. for C12H10NaO2P: C, 60.01; H, 4.20; P, 12.90. Found: C, 55.25, 55.47; H, 4.22, 4.20; P, 11.06, 11.15.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[O:38][CH:39]([CH3:41])[CH3:40].[Cl:42][C:43]1[C:44]([C:53]([F:56])([F:55])[F:54])=[N:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=1[CH3:48]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:50](=[O:51])[CH2:49][N:46]3[C:47]([CH3:48])=[C:43]([Cl:42])[C:44]([C:53]([F:56])([F:55])[F:54])=[N:45]3)[CH2:36][CH2:37]2)=[CH:28][C:27]=1[O:38][CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)Oc1cc(N2CCNCC2)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)c(OC(C)C)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-3-isopropoxy-phenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.21 (d, 1H), 6.71 (s, 1H), 6.53 (d, 1H), 5.38 (s, 2H), 4.66 (m, 1H), 3.58 (m, 4H), 3.25 (m, 2H), 3.15 (m, 2H), 2.18 (s, 3H), 1.26 (d, 6H) ppm; MS (ES) M+H expected=479.1, found=479.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][C:17]([C:20]([CH2:23][O:24][C:25](=[O:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])([CH3:22])[CH3:21])=[N:18][N:19]=1>C1(C)C=CC=CC=1.CCCCC>[C:28]([O:27][CH2:26][C:25]([O:24][CH2:23][C:20]([C:17]1[S:16][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:19][N:18]=1)([CH3:22])[CH3:21])=[O:31])(=[O:30])[CH3:29]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC(=O)OCC(=O)OCC(C)(C)c1nnc(N)s1
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: COc1cccc(OC)c1C(=O)Nc1nnc(C(C)(C)COC(=O)COC(C)=O)s1
Temperature: 25 °C
Yield: 3 %

Procedure:
A solution of 300 mg of 2,6-dimethoxybenzoyl chloride in 20 ml of toluene containing 300 mg of 2-amino-5-[(2-acetoxy-1-acetoxymethyl)-1-methylethyl]-1,3,4-thiadiazole was heated at reflux for eighteen hours. The reaction mixture was cooled to room temperature and diluted with pentane. A solid precipitate which formed was collected by filtration and air dried to give N-[5-((2-acetoxy-1-acetoxymethyl)-1-methylethyl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide in 3% yield.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]=[C:5]([C:7]1[C:8](=[O:29])[O:9][C:10]2[C:20]([CH3:21])=[C:19]([O:22]C3CCCCO3)[CH:18]=[CH:17][C:11]=2[C:12]=1[O:13][CH2:14][CH:15]=[CH2:16])[CH3:6].O1CCCC1>CCCCCC.C(OCC)(=O)C>[OH:22][C:19]1[CH:18]=[CH:17][C:11]2[C:12]([O:13][CH2:14][CH:15]=[CH2:16])=[C:7]([C:5](=[N:4][O:3][CH3:2])[CH3:6])[C:8](=[O:29])[O:9][C:10]=2[C:20]=1[CH3:21]
Reactant: C=CCOc1c(C(C)=NOC)c(=O)oc2c(C)c(OC3CCCCO3)ccc12
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOc1c(C(C)=NOC)c(=O)oc2c(C)c(O)ccc12
Reaction time: 7 h

Procedure:
10 ml of a 1M aqueous solution of hydrochloric acid is added to a solution containing 1 g of the product prepared in Stage C and 20 ml of tetrahydrofuran. Agitation is carried out for 7 hours at ambient temperature followed by dilution with 50 ml of a hexane-ethyl acetate mixture (1-1). The phases are separated and the aqueous phase is extracted with a hexane-ethyl acetate mixture (1-1). The organic phases are combined and washed with a 1M solution of sodium dihydrogen phosphate, followed by drying, filtering and concentrating to dryness. The residue is triturated with a hexane-ethyl acetate mixture (4-1). After separating and drying 770 mg of product is collected.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[B:16]([OH:17])[O:15][CH2:14][C:13]=3[CH:18]=2)=[C:6]([OH:21])[CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:2][C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[B:16]([OH:17])[O:15][CH2:14][C:13]=3[CH:18]=2)=[C:6]([OH:21])[CH:5]=1)=[O:3])[CH3:29]
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Yield: 77 %

Procedure:
A mixture of 5-(4-carboxy-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1.95 g, 6.82 mmol) and sulfuric acid (1.5 mL) in ethanol (75 mL) was refluxed for 6 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure. Silica gel column (6:4 to 5:5 hexane/acetone) followed by recrystallization from diisopropyl ether gave 5-(4-Ethoxycarbonyl-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1.65 g, 77%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:24][O:25][C:26]1[CH:32]=[C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][C:27]=1[NH2:28].CO>CC1C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1.C(Cl)Cl>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15]([NH:28][C:27]2[CH:29]=[CH:30][C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:32][C:26]=2[O:25][CH3:24])[N:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1C(=O)NC
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2ccc(N3CCOCC3)cc2OC)ncc1C(=O)NC
Temperature: 100 °C

Procedure:
To a solution of 4-(2-acrylamidophenylamino)-2-chloro-N-methylpyrimidine-5-carboxamide (40 mg, 0.12 mmol) in 0.08M p-TSA/1,4-dioxane (5 mL), 2-methoxy-4-morpholinoaniline (25.13 mg, 0.12 mmol) was added and heated at 100° C. for 1 h. TLC showed completion of starting material (TLC system: 5% methanol in DCM (Rf): 0.3). 1,4 dioxane was evaporated, and the residue was diluted with ethyl acetate (15 mL) and washed with water (2×5 mL). The organic layer was separated, dried over sodium sulphate, and concentrated. Crude compound was purified by column chromatography using silica gel (100-200 mesh) with 2% methanol in DCM to obtain 4-(2-acrylamidophenylamino)-2-(2-methoxy-4-morpholino phenylamino)-N-methylpyrimidine-5-carboxamide as off white solid. Yield: (8 mg, 13%). MS: m/z 504.3 (ES+, M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:49].[ClH:49].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][NH:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CCNC2
Yield: 51 %

Procedure:
tert-Butyl 9-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.2 g, 2.4 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (550 mg, 51%) as a yellow solid: mp 280-295° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.67 (s, 2H), 7.59-7.52 (m, 3H), 7.35-7.27 (m, 4H), 7.24-7.17 (m, 1H), 7.01 (dd, J=7.4, 2.0 Hz, 1H), 6.38-6.27 (m, 2H), 4.45 (s, 2H), 3.67 (s, 3H), 3.42 (t, J=6.4 Hz, 2H), 2.97-2.89 (m, 4H), 2.81-2.76 (m, 2H); ESI MS m/z 384 [M+H]; HPLC (Method B)>99% (AUC), tR=13.3 min.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1.C(Cl)Cl>O>[Br:7][C:8]1[N:13]=[CH:12][C:11]([O:14][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Br)nc2)n1
Temperature: 125 °C

Procedure:
To a slurry of cesium carbonate (8.9 g, 27 mmol) and 6-bromopyridin-3-ol (2.6 g, 15 mmol) was added 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.0 g, 14 mmol). The reaction mixture was sealed and heated to 125° C. for 16 h. The mixture was cooled and diluted with water and the aqueous solution was extracted with DCM (3×75 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil, which was taken up in a little DCM and purified on an ISCO 120 g column, eluting with a gradient of 0-100% EtOAc/DCM, to afford 4-(2-(6-bromopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine as an off-white solid. MS m/z=295 [M+H]+. Calc'd for C15H12BrN5O: 358.2.