Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[CH:25][CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18]([CH:24]=[CH:25][CH3:26])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:27]
Reactant: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
The mixture 2-[3-methyl-2-(1-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (142) (340 mg, 0.94 mmol) and KOH (700 mg, 12.5 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (143) as white solid (315 mg, 100%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.[Cl:15][C:16]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:16]=1[Cl:15]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1Cc1cccc(Cl)c1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 78 and 2,3-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Br.[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=[O:36])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1>[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]([OH:36])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:6]2)[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1ccccc1OCC1CCCCC1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1OCC1CCCCC1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
10 ml of tetrahydrofuran was cooled to −78° C., 5.11 ml of n-butyllithium (1.6 M, hexane solution) was added thereto, and the mixture was stirred. A solution of 2.000 g of (2-cyclohexylmethyloxy)bromobenzene dissolved in 5 ml of tetrahydrofuran was added dropwise thereinto. After one hour, a solution of 1.93 g of 1-benzyl-4-piperidineacetaldehyde dissolved in 5 ml of tetrahydrofuran was added dropwise thereinto, and the mixture was further stirred for one hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (n-hexane:ethyl acetate=4:1), to give 2.986 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[N:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:8][C:6]1[CH:7]=[C:2]([C:13]2[S:9][C:10]([C:14]3[N:19]=[C:18]([C:20]4[N:21]=[CH:22][CH:23]=[CH:24][N:25]=4)[CH:17]=[CH:16][CH:15]=3)=[N:11][CH:12]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Fc1cncc(Br)c1
Reactant: c1cnc(-c2cccc(-c3nccs3)n2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cncc(-c2cnc(-c3cccc(-c4ncccn4)n3)s2)c1

Procedure:
Under argon, 88 mg (0.50 mmol) of 3-bromo-5-fluoropyridine, 120 mg (0.50 mmol) of 2-[6-(1,3-thiazol-2-yl)pyridin-2-yl]pyrimidine (cf. Example K, step 1), 326 mg (1.0 mmol) of cesium carbonate and 8 mg (0.01 mmol) of [(t-Bu)2P(OH)]2PdCl2 (“POPd”) in 10 ml of N,N-dimethylformamide were stirred at 120° C. for 16 hours. For work-up, the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and water and the organic phase was dried, concentrated under reduced pressure and purified by column chromatography on silica gel RP-18 (mobile phase: water/acetonitrile/formic acid). This gave 11 mg (7% of theory) of 2-{6-[5-(5-fluoropyridin-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:42](O)(C(F)(F)F)=[O:43]>CN(C=O)C>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH:42]=[O:43])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(C=O)CC3)cc2)cc1NCc1cccc(F)c1F

Procedure:
Compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (70 mg, 0.15 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for two days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (41 mg). MS found for C25H25F2N5O2 as (M+H)+ 466.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.15 (1H, s), 8.06 (1H, s), 7.33 (2H, dt, J=8.8; 2.0 Hz), 7.28 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.80 (1H, s), 4.56 (2H, s), 4.48 (1H, m), 3.86 (1H, m), 3.27 (1H, m), 2.93 (1H, m), 2.82 (1H, m), 1.94 (2H, m), 1.64 (2H, m) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:16][C:17]1[C:18]([CH3:41])=[C:19]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=2)[C:20]([CH3:32])=[C:21]([Cl:31])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[Cl:31][C:21]1[C:20]([CH3:32])=[C:19]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][O:1][C:2]3[CH:15]=[CH:14][C:5]4[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[CH:34]=2)[C:18]([CH3:41])=[C:17]([Cl:16])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: Cc1c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.237 g, 1.14 mmol), {3′,5′-dichloro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.475 g, 1.14 mmol) and tributylphosphine (0.453 mL, 1.82 mmol) in toluene (18 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.459 g, 1.82 mmol) was added, and the mixture was stirred at room temperature for 1 hr under nitrogen atmosphere. Hexane (9 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.622 g, yield 89%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17]O)=[CH:11][CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][Br:48])=[CH:11][CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH3:2]
Reactant: CCOC(=O)NC1CCc2ccc(CCO)cc2C1Cc1cccc(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(CCBr)cc2C1Cc1cccc(Cl)c1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of [1-(3-chloro-benzyl)-7-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]carbamic acid ethyl ester (554 mg, 1.428 mmol) in 15 ml dry CH2Cl2 cooled to 0° C. was added triphenylphosphine (562 mg, 2.142 mmol) and carbon tetrabromide (0.208 ml, 2.142 mmol). The mixture was stirred for 1 h, after which solvents were evaporated. The residue was purified by chromatography to obtain 277 mg of product as a white solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=O.[CH:7](=[O:10])[CH2:8][CH3:9].C(OC(=O)C)(=O)C>C1CCCCC1.N(CC(O)=O)C>[CH:7](/[C:8](/[CH3:9])=[CH:2]\[C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: COC(=O)C=O
Reactant: CCC=O
Agent: CNCC(=O)O
Solvent: C1CCCCC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)/C=C(/C)C=O
Yield: 68.9 %

Procedure:
18 g (0.2 mol) of sarcosine were suspended by stirring in 500 ml of cyclohexane in a flask and, starting at 20° C., a mixture of 1809 g (20.6 mol) of methyl glyoxylate and 1194 g (20.6 mol) of propionaldehyde was added within 90 min. During the dropwise addition the temperature rose slowly to the boiling point (75° C.). After the addition was complete, initially a small amount of water was removed as azeotrope, and then the mixture was distilled until the bottom temperature was 100° C. to remove cyclohexane. Then 2220 g (21.8 mol) of acetic anhydride were added to the residue, and the reaction mixture was distilled to a bottom temperature of 150° C. to remove acetic acid. Fractional distillation of the bottom product yielded 1822 g (14.2 mol) of methyl 3-formylcrotonate, corresponding to a yield of 69% of theory, with a trans/cis isomer ratio of 93/7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[Br:16]Br.C(=O)(O)[O-].[Na+]>CCOCC>[Br:16][CH2:14][C:13]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:7][C:2]=1[F:1])=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCCCCl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1ccc(OCCCCl)cc1F
Reaction time: 17 h

Procedure:
A solution of the product of Step A (2.3 g) in ether (10 mL) was treated with bromine (0.51 mL) and the mixture stirred for approximately 17 hours. The mixture was slowly poured into saturated sodium bicarbonate solution (40 mL) and then the organic layer was separated. The aqueous layer was washed with a fresh portion of ether (40 mL). The combined organic layers were washed with a fresh portion of water (50 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound (3.1 g).
Reaction SMILES: [Na].C(O)(=O)C.[CH:6]([NH2:8])=[NH:7].[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16](=[CH:19]N(C)C)[CH:17]=O)=[CH:13][CH:12]=1.[O-]CC.[Na+]>C(O)C>[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:17]=[N:7][CH:6]=[N:8][CH:19]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(OC(C=O)=CN(C)C)cc1
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(Oc2cncnc2)cc1
Reaction time: 40 h
Yield: 64.8 %

Procedure:
Sodium metal (4.1 g) was dissolved in absolute ethanol (90 ml) and formamidine acetate (18.4 g) and 2-(p-methoxyphenoxy)-3-(dimethylamino)acrolein (13.0 g) were added to the ethanolic solution of sodium ethoxide. The mixture was heated under reflux, with stirring, for 40 hr and then the solvent was removed, by distillation under reduced pressure. The residue was treated with water (200 ml) and chloroform (200 ml), the chloroform layer was separated and the chloroform removed by distillation under reduced pressure. The residue was purified by column chromatography over silica gel using chloroform as eluent to give 5-(p-methoxyphenoxy)pyrimidine as an oil (7.7 g) which was characterised by p.m.r. spectroscopy.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[ClH:24].[CH3:25][O:26][C:27]([CH2:29][CH2:30][NH2:31])=[O:28].C(N(C(C)C)C(C)C)C>CN(C)C=O>[ClH:24].[O:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:13]([CH2:12][CH2:11][NH:31][CH2:30][CH2:29][C:27]([O:26][CH3:25])=[O:28])[CH2:14]1
Reactant: COC(=O)CCN
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
33.2 g (0.1 mol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, 14.0 g of N-(2-methoxycarbonylethyl)-amine hydrochloride and 39 g of N-ethyl-N,N-diisopropylamine are dissolved under nitrogen in 750 ml of dimethylformamide and the solution is stirred for 16 hours at room temperature. The reaction mixture is subsequently concentrated to approximately 200 ml under reduced pressure, 500 ml of water are then added and the whole is extracted by shaking three times with 150 ml of dichloromethane each time. The combined organic phases are dried over sodium sulphate and concentrated to dryness by evaporation. By adding ethanolic hydrochloric acid and cooling, N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride having a melting point of 190°-192° is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].N[C@@H:14](CCC)C(O)=O.C(N)(C)C>>[NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:14])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCC[C@H](N)C(=O)O
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Solvent: CC(C)N
Product: CCC[C@H](N)[C@H](O)C(=O)NC(C)C

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using (S)-2-aminopentanoic acid in the first step (step B1), and isopropylamine in the seventh step (step B7).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.Cl.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19])([O-:14])=[O:13].C(N(CC)CC)C>CCCCO>[Cl:9][C:6]1[N:5]=[C:4]([NH2:10])[N:3]=[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:7]=1[NH2:8]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(N)c(NCc2cccc([N+](=O)[O-])c2)n1
Yield: 78.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine-2,5-diamine (700 mg, 3.91 mmol), 3-nitrobenzylamine hydrochloride (885 mg, 4.69 mmol) and triethylamine (1.6 mL, 11.7 mmol) in n-BuOH (20 mL) was refluxed for 17 h, concentrated in vacuo and the residue partitioned between EtOAc (10 mL) and H2O (5 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound as an orange solid (906 mg, 76%) which was used in the next reaction without further purification; NMR δH (400 MHz, CDCl3) 8.16 (1H, s), 8.10 (1H, d, J 8.0 Hz), 7.80 (1H, d, J 7.5 Hz), 7.62 (1H, t, J 7.5 Hz), 7.25 (1H, t, J 6.0 Hz), 5.69 (2H, s), 4.67 (2H, d, J 6.0 Hz) and 3.93 (2H, br s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][C:10]=1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:21]([O-])=O.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([N:15]=[N+:16]=[N-:21])=[O:14])=[CH:11][C:10]=1[Cl:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 5 °C
Yield: 96.8 %

Procedure:
4-Benzyloxy-3-chlorobenzoic acid hydrazide (27.6 g., 0.1 mole) is suspended in 500 ml. 1N hydrochloric acid and the mixture cooled to about 0° C. A solution of sodium nitrite (7.0 g.) in 40 ml. water is added at such a rate as to keep the temperature below 5° C. The mixture is stirred at 5° C for 3/4 hr., filtered and the precipitate dried in vacuo to give 27.8 g., (96.8% yield) 4-benzyloxy-3-chlorobenzoyl azide.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12](O)=[O:13])=[CH:7][C:6]=2[CH:15]=1.S(Cl)([Cl:19])=O>CN(C)C=O>[OH:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12]([Cl:19])=[O:13])=[CH:7][C:6]=2[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2cc(O)c(O)cc2oc1=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2cc(O)c(O)cc2oc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6,7-dihydroxy-2-oxo-2H-1-benzopyran-3-carboxylic acid (110 mg), thionyl chloride (5 mL), and dimethylformamide (one drop) was stirred for 2 hours at room temperature. The excess thionyl chloride was distilled off in vacuo. Benzene (20 mL) was added, followed by vacuum distillation and vacuum drying, to yield 6,7-dihydroxy-2-oxo-2H-1-benzopyran-3-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Cl:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][N:23]2[C@H:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34]>C(Cl)Cl>[Cl:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][N:23]2[C@@H:29]([CH2:33][CH2:32][OH:31])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:34]
Reactant: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)[C@H](CCO)N1CCc2c1ccc(F)c2Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Prepared using general procedure 60: To a solution of aniline (1.4 mL, 15.6 mmol) in CH2Cl2 (37 mL) under nitrogen at RT was added a solution of trimethylaluminum in hexane (2.0 M, 7.8 mL, 15.6 mmol) over 5 min. After stirring at RT for 20 min, a solution of (S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one (4.0 g, 15.6 mmol) in CH2Cl2 (37 mL) was added over 10 min. Heated to reflux for 12 h, then the reaction mixture was cooled to 0° C. and quenched by careful addition of aqueous 1M HCl (70 mL). Phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×75 L). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 2-7.5% MeOH in CH2Cl2 gave (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide as a white solid (5.44 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.59 (d, J=7.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.07-6.99 (m, 2H), 6.53 (dd, J=3.6, 8.6 Hz, 1H), 4.70 (t, J=4.9 Hz, 1H), 4.35 (t, J=7.4 Hz, 1H), 3.92-3.80 (m, 1H), 3.68-3.62 (m, 1H), 3.55-3.47 (m, 2H), 3.05-2.89 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.88 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=349.1; tR=1.69 min.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:22][C:23]1[C:28](O)=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33]>ClCCl>[Cl:22][C:23]1[C:28]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33]
Reactant: N#CCC(=O)O
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17 g. (0.2 moles) of cyanoacetic acid are dissolved in 150 ml. of dichloromethane and 40 g. (0.2 moles) of dicyclohexylcarbodiimide and 52 g. (0.2 moles) of pentachlorophenol dissolved in 200 ml. of dichloromethane are added dropwise at room temperature. The mixture is stirred for 4 hours at room temperature. The mixture is cooled to 0° C. and the precipitated dicyclohexylcarbodiimide is filtered and the solvent is distilled off. The residue is taken up in diisopropyl ether, filtered and dried.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCN(C(OC(C)(C)C)=O)CC3)=C(C)C=2N=1.Cl.[CH3:33][O:34][C:35]1[N:40]=[C:39]([O:41][CH3:42])[C:38]([C:43]2[N:44]=[C:45]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[C:46]3[S:51][C:50]([CH2:52][N:53]4[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)=[C:49]([CH3:59])[C:47]=3[N:48]=2)=[CH:37][N:36]=1.[C:66](O)(=[O:70])[C@H:67]([CH3:69])[OH:68]>>[CH3:33][O:34][C:35]1[N:40]=[C:39]([O:41][CH3:42])[C:38]([C:43]2[N:44]=[C:45]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[C:46]3[S:51][C:50]([CH2:52][N:53]4[CH2:58][CH2:57][N:56]([C:66](=[O:70])[C@@H:67]([OH:68])[CH3:69])[CH2:55][CH2:54]4)=[C:49]([CH3:59])[C:47]=3[N:48]=2)=[CH:37][N:36]=1
Reactant: C[C@H](O)C(=O)O
Reactant: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)c(C)c3n2)c(OC)n1
Agent: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)c(OC)n1

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (75 mg) was reacted with 2,4-dimethoxypyrimidin-5-yl-5-boronic acid via General Procedure A. This crude intermediate was subjected to General Procedure D in which the crude HCl salt of 2-(2,4-dimethoxypyrimidin-5-yl)-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine was reacted with L-Lactic acid via General Procedure B to give 17.2 mg of 406 after reverse phase HPLC purification. MS (Q1) 544.2 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[F:21][C:22]([F:28])([CH:25]([F:27])[F:26])CI>O>[N+:11]([C:3]1[CH:4]=[C:5]([S:8][CH2:9][C:25]([F:27])([F:26])[CH:22]([F:28])[F:21])[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: FC(F)C(F)(F)CI
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(SCC(F)(F)C(F)F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. of dimethylformamide is treated under nitrogen with 0.97 g. of sodium borohydride in 10 ml. of dimethylformamide at 20°-30° C. After 1 hour at 20°-25° C, 6 g. of 2,2,3,3-tetrafluoro-1-iodopropane is added and the mixture is heated at 100° C for 4 hours. The mixture is cooled, diluted with water and extracted with chloroform. Evaporation of the dried chloroform solution yields 2-nitro-4-(2,2,3,3-tetrafluoropropylthio)aniline as an oil. Acetylation of the latter compound in acetic anhydride with sulfuric acid catalysis according to the first paragraph of Example XXI yields 1-acetamido-2-nitro-4-(2,2,3,3-tetrafluoropropylthio)benzene which can be isolated by extraction into chloroform. Alternatively, this may be prepared by substituting 1-acetamido-2-nitro-4-thiocyanatobenzene in the above alkylation reaction.