Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:11](O)(=O)C>O>[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:11]
Reactant: CC(=O)O
Reactant: COC(=O)c1cccnc1
Solvent: O
Product: CC(=O)c1cccnc1

Procedure:
A mixture of 22 g/h of methyl nicotinate, 57 g/h of acetic acid and 20 g/h of water was evaporated in an evaporator and passed, together with 10 l/h of nitrogen, at 400° C., over 100 ml of catalyst E, which contained 2% by weight of sodium oxide, the remainder being anatase. The catalyst was prepared similarly to Example 8, by impregnating 980 g of TiO2 carrier I with a solution which contained 20 g of Na2O (as aqueous NaOH). The reaction gases were then cooled and were collected in a receiver. From the discharged two-phase mixture, the organic phase was analyzed by gas chromatography. The conversion of nicotinic ester and of acetic acid was 100% in each case. The selectivity with respect to 3-acetylpyridine was 60%. In addition, pyridine was formed with a selectivity of 29%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[NH4+:14]>CN(C)C=O>[CH:7]1[C:6]([C:10]([NH2:14])=[O:12])=[CH:5][C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8.06 gm (50 mmol) indole-5-carboxylic acid in 150 ml dimethylformamide were added 8.11 gm (50 mmol) carbonylidiimidazole and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was then added dropwise to 150 ml concentrated ammonium hydroxide and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to give a viscous oil which was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing 0-10% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give the title compound as an oil which crystallizes upon standing.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]2=[O:31])[CH:19]=[CH:20][C:21]=1[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([CH3:15])[CH:17]=2)[C:24]1=[O:31])=[O:29]
Reactant: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1C
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1C
Yield: 51.8 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3,4-dimethylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.105 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.090 g (52%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3,4-dimethylphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]2[N:43]=[C:42](Cl)[N:41]=[C:40]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]3[CH2:55][C:54]([CH3:57])([CH3:56])[N:53]([O:58][CH:59]4[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]4)[C:52]([CH3:66])([CH3:65])[CH2:51]3)[N:39]=2)[N:3]=1.[CH2:67]([CH2:69][NH2:70])[OH:68]>>[OH:68][CH2:67][CH2:69][NH:70][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][C:15]([CH3:29])([CH3:28])[N:16]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:17]([CH3:19])([CH3:20])[CH2:18]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]2[N:43]=[C:42]([NH:70][CH2:69][CH2:67][OH:68])[N:41]=[C:40]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]3[CH2:55][C:54]([CH3:56])([CH3:57])[N:53]([O:58][CH:59]4[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]4)[C:52]([CH3:65])([CH3:66])[CH2:51]3)[N:39]=2)[N:3]=1
Reactant: NCCO
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCCCNc3nc(Cl)nc(NCCCCC4CC(C)(C)N(OC5CCCCC5)C(C)(C)C4)n3)n2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(CCCCNc2nc(NCCO)nc(NCCCCCCNc3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OC5CCCCC5)C(C)(C)C4)n3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of N,N'-bis{2-chloro-4-[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: C([O:5][C:6](=[O:22])/[CH:7]=[CH:8]/[C:9]1[CH:21]=[N:20][C:12]2[NH:13][C:14](=[O:19])[CH2:15][N:16]([CH3:18])[CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:16]1[CH2:17][C:11]2[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:22])=[O:5])[CH:21]=[N:20][C:12]=2[NH:13][C:14](=[O:19])[CH2:15]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)OC(C)(C)C)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 163.9 %

Procedure:
A suspension of (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid tert-butyl ester (0.59 g, 1.9 mmol) in CH2Cl2 (7 mL) was treated with TFA (7 mL). After stirring at room temperature under N2 for 45 min, the clear tan solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl in dioxane (10 mL, 4.0 M) and sonicated until the oil was converted to a fine off-white solid. After stirring under N2 for 20 min, the solid was isolated by filtration, washed with Et2O, and dried under vacuum for several hours to give the title compound (0.77 g, quantitative) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.27 (bs, 1H), 11.28 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.32 (d, J=1.9 Hz, 1H), 7.65 (d, J=16.1 Hz, 1H), 6.63 (d, J=16.1 Hz, 1H), 4.32 (s, 2H), 3.82 (s, 2H), 2.89 (s, 3H); MS (ESI) m/e 248 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[C:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)[CH:14]=[CH:15][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:25]([O-:30])([N+]([O-])=O)=[O:26].C(Cl)(Cl)Cl.Cl>[OH-].[Na+]>[N+:25]([C:8]1[O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=3)=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:30])=[O:26]
Reactant: O=C(O)c1ccc(-c2ccc3occ(-c4ccccc4)c3c2)cc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(-c2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)cc1

Procedure:
A solution of 3.1 g. (0.01 mole) of the product of step D and 2 g. of dinitrogen tetraoxide in 250 ml. of chloroform is stirred at about 20° C. for about 16 hours. Evaporation of the mixture provides a residue which is dissolved in 10 percent sodium hydroxide solution, then acidified with hydrochloric acid. The precipitate is collected by filtration, dissolved in a chloroform/ethanol mixture and chromatographed on silica gel, eluting with chloroform. The solid obtained is recrystallized twice from a mixture of water and N,N-dimethylformamide to provide yellow crystals of 4-(2-nitro-3-phenylbenzofuran-5-yl)benzoic acid, m.p. 259°-261° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.Br[CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:35]([CH2:34][N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]1=2)#[N:36]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)NC(=O)CO3)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC#N)C(=O)CO3)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
A mixture of tert-butyl 4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamate (70 mg, 0.162 mmol), 2-bromoacetonitrile (58.4 mg, 0.487 mmol) and potassium carbonate (67.3 mg, 0.487 mmol) in DMF (2 ml) was stirred at 40° C. for 16 h. The reaction mixture was cooled and diluted with water (10 ml) and extracted with DCM (8 mlX3). The combined organic phase was concentrated and the residue was purified by column (biotage, 10 g) eluted with Ethyl acetate/cyclohexane 0-30% to give product 12 mg. 1H NMR (500 MHz, CDCl3) 7.29 (s, 1H), 7.19-7.26 (m, 5H), 7.13 (m, 2H), 7.05 (d, 2H), 4.88 (s, 2H), 4.81 (s, 2H), 4.73 (br, 1H), 4.21 (d, 2H), 1.38 (br, 9H). LCMS (Method D): RT=1.35 min, M+H+=472.2.
Reaction SMILES: [CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10](S(C)(=O)=O)[C:9]([C:16]#[N:17])=[CH:8][N:7]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.[NH2:28][C@H:29]1[CH2:34][C@@H:33]([OH:35])[C@H:32]([CH3:36])[CH2:31][CH2:30]1>>[OH:35][C@H:33]1[C@H:32]([CH3:36])[CH2:31][CH2:30][CH:29]([NH:28][C:10]2[C:9]([C:16]#[N:17])=[CH:8][N:7]=[C:6]([NH:5][C:2]3([CH3:1])[CH2:4][CH2:3]3)[N:11]=2)[CH2:34]1
Reactant: CC1(Nc2ncc(C#N)c(S(C)(=O)=O)n2)CC1
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC(Nc2nc(NC3(C)CC3)ncc2C#N)C[C@H]1O
Temperature: 90 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To the reaction mixture of 2-(1-methylcyclopropylamino)-4-(methylsulfonyl)pyrimidine-5-carbonitrile from the previous step was added DIEA (2.14 mL, 12.22 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (0.371 g, 2.241 mmol; synthesis described herein). The reaction was stirred at 90° C. for 16 h. Upon completion of reaction, as indicated by LCMS and TLC, the reaction mixture was concentrated and purified by silica gel chromatography using a gradient of 0%-60% ethyl acetate in hexanes. The product fractions were combined and concentrated to afford 4-((3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carbonitrile (0.185 g, 30% yield) as a pale yellow solid. MS (ESI) m/z 302.1 [M+1]+
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:15])[C:11]=1[O:12]CC)[CH:7]=[O:8])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:15])[C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)cc(F)c1OCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1cc(C=O)cc(F)c1O
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To the solution of 3,4-diethoxy-5-fluorobenzaldehyde (300 mg, 1.4 mmol) in DCM (50 mL) was added AlCl3 (207 mg, 1.55 mmol), and at 0° C., pyridine (230 mg, 2.8 mmol) was added, and the resulting mixture was refluxed overnight. The reaction mixture was cooled to room temperature, poured into ice water solution, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography on silica gel to give 3-ethoxy-5-fluoro-4-hydroxybenzaldehyde (160 mg).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)o1
Reaction time: 2 h

Procedure:
A solution of 100 mg of methyl 5-nitro-2-furoate (Lancaster Synthesis, Windham, N.H., USA) in 20 ml of EtOAc was stirred with 20 mg of Pd/C (10%) under one atmospheric pressure of hydrogen gas. After at RT for 2 hours, the mixture was filtered through a celite pad and concentrated. Pure methyl 5-amino-2-furoate was obtained by purification on a fresh silica gel column eluted with 30% EtOAc in hexane.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3Cl)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3Cl)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 65 mg (0.14 mmol) 6-{[6-(2-chlorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 2.5 ml dioxan and add 0.5 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.5 ml 1 N hydrochloric acid and 6 ml ethyl acetate. Separate the organic phase, dry over sodium sulphate, filter and concentrate by evaporation. 44 mg (70% of theor.) of the target compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[N+:7]=1[O-:8].[NH3:13]>C(O)C>[NH2:13][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[N+:7]=1[O-:8]
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Reactant: N
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])cc(N)[n+]1[O-]
Yield: 41 %

Procedure:
A reaction solution consisting of 5.66 g. (0.03 mole) 6-chloro-4-nitro-2-picoline-1-oxide and 100 ml. ethanol was saturated with anhydrous ammonia and sealed in a strong bottle. This reaction mixture was heated and maintained at a temperature in the range of 100° to 105° C. for 21 hrs. The bottle and contents were then cooled and the seal was broken. Crystals had formed. The crystals were collected on a filter and washed with a small amount of cold ethanol. Recrystallization from 95% aqueous ethanol yielded 2.06 g. (41% yield) of 6-amino-4-nitro-2-picoline-1-oxide as yellow needles having a melting point at 221° to 222° C. (with decomposition). When a small sample was mixed with ethanolic ferric chloride a blue solution was obtained.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH:7]1[CH2:12][CH:11]2[CH2:13][CH:9]([C:10]2([CH3:15])[CH3:14])[C:8]1=[CH2:16])C.[OH-].[Na+]>C(O)C>[CH3:14][C:10]1([CH3:15])[CH:9]2[CH2:13][CH:11]1[CH2:12][CH:7]([CH2:6][CH2:5][C:4]([OH:17])=[O:3])[C:8]2=[CH2:16]
Reactant: C=C1C(CCC(=O)OCC)CC2CC1C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C1C(CCC(=O)O)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
(6,6-Dimethyl-2-methylene-bicyclo[3.1.1]hept-3-ylmethyl)-acetic acid ethyl ester (3.25 g, 14.6 mmol) was dissolved in absolute ethanol (50 ml). To this solution was added 1.0 N NaOH (20 ml). After stirring for 18 hours at ambient temperature, the reaction was then concentrated to 20 ml and partitioned between 0.1 N HCl and CH2Cl2. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated under vacuum to give 2.79 g of the titled compound: C.I. m/z 195.1 [M+1]; 1H NMR (CDCl3)δ 4.78 (s, 1H), 4.77 (s, 1H), 3.02 (s, 1H), 2.75 (dd, J=4.9, 15.3 Hz, 1H), 2.56 (d, J=10.9 Hz, 1H), 2.49 (t, J=6.1 Hz, 1H), 2.38 (m, 1H), 2.24 (dt, 2.1, 12.0 Hz, 1H), 2.02 (m, 1H), 1.57 (dt, J=3.2,14.0 Hz, 1H), 1.26 (s, 3H), 1.19 (d, J=10.1,1H), 0.77 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:12]1[C:17]([C:18]([CH2:20]Br)=O)=[CH:16][CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C>[N+:22]([C:14]1[CH:15]=[CH:16][C:17]([C:18]2[N:1]=[C:2]3[N:6]([CH:20]=2)[C:5]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:4]=2[S:3]3)=[CH:12][CH:13]=1)([O-:24])=[O:23]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc2ccc(O)cc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1

Procedure:
2-Amino-6-hydroxybenzothiazole, 2-Bromo-4-nitroacetophenone and absolute Ethanol are added together and heated to reflux for approximately 24 hours. Tetrabutylammonium iodide is added and the reaction is refluxed an additional 12 hours. The resulting yellow suspension is cooled and the solids collected and washed with Ethanol and Diethyl ether. The solids are dried under vacuum to give Intermediate 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH:29]3C)=[O:27])[N:9]=2)[CH:7]=1.[CH3:40]C1NCCN(C(OC(C)(C)C)=O)C1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:38])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH:32]([CH3:40])[CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CC1CN(C)CCN1C(=O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Product: CC1CN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CCN1C

Procedure:
Using synthetic method analoguous that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from tert-butyl 3-methylpiperazine-1-carboxylate. LCMS (Method 20) [M+H]+=559.2, RT=2.23 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5 Hz, 7.2 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.35-5.13 (m, 2H), 4.18-4.02 (m, 1H), 3.86-3.78 (m, 1H), 3.26-3.10 (m, 1H), 2.84-2.73 (m, 2H), 2.26-1.91 (m, 5H), 1.01 (d, 3H, J=6.0 Hz).
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])([O-])=O.CO>[Pd]>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6]
Reactant: CC(C[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(CN)c1ccccc1
Reaction time: 24 h
Yield: 96 %

Procedure:
Under argon atmosphere, 121 mg of optically active 1-nitro-2-phenylpropane (732 μmol) were dissolved in 5 mol of dry methanol and 50 mg of palladium on charcoal (10%) were added thereto. The obtained suspension was vigorously stirred under hydrogen atmosphere for 24 hours. The mixture was filtered and the solid was washed with methanol. The solvent was evaporated and the residue was dissolved in 2 ml of benzene. The solvent was evaporated to give 95 mg of an optically active 1-amino-2-phenylpropane as a colorless oil (703 μmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].Cl[CH2:8][C:9]1[CH:39]=[CH:38][C:12]([C:13]([NH:15][C:16]2[S:17][C:18]3[C:24]([C:25]4[N:26]=[C:27]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[S:28][CH:29]=4)=[CH:23][CH:22]=[C:21]([O:36][CH3:37])[C:19]=3[N:20]=2)=[O:14])=[CH:11][CH:10]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[S:17][C:18]3[C:24]([C:25]4[N:26]=[C:27]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[S:28][CH:29]=4)=[CH:23][CH:22]=[C:21]([O:36][CH3:37])[C:19]=3[N:20]=2)=[O:14])=[CH:38][CH:39]=1)[CH3:6]
Reactant: COc1ccc(-c2csc(N3CCOCC3)n2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: CNCCOC
Solvent: C1CCOC1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(-c4csc(N5CCOCC5)n4)c3s2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
0.035 g N-(2-methoxyethyl)-methylamine (0.00039 Mol) and 0.064 g (4-chloromethyl-N-[4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-yl]-benzamide (0.00013 Mol) dissolved in THF (2 ml) were heated to reflux for 4 hrs. After cooling to room temperature and evaporation of the solvent the residue was triturated with water (7 ml). A precipitation formed, which was filtered, washed with water and dried yielding the title product as an off-white solid (79%); F.p.: 100-110° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]O)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:25]>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Br:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](COCc1ccccc1CO)NC(=O)OC(C)(C)C
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC[C@H](COCc1ccccc1CBr)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 161.9 %

Procedure:
A solution of compound 18i (3.0 g, 9 mmol) in CCl4 (10 mL) was cooled in an ice bath. To this mixture was added PBr3 (1.0 g, 4.5 mmol) dropwise and the mixture was stirred at 0° C. for 2 hr. The mixture was quenched with water and extracted with DCM (3×50 mL). The combined organic layers were washed with brine and concentrated. The crude compound 18j (2.8 g, 80% yield) was used in the next step without purification. LCMS (m/z): 385.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:13]=1[NH2:24].[C:25](OC)(=[O:29])[C:26]([CH3:28])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:24]=[C:26]([CH3:28])[C:25](=[O:29])[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)=O
Reactant: COCC(C)Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N
Product: COCC(C)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-Chloro-4-difluoromethoxy-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.149 g, 0.42 mmol) and methyl pyruvate (75 μL, 0.83 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 121a): 1H NMR (300 MHz, CDCl3): δ 8.54–8.53 (d, 1H, J=4.8 Hz), 7.34–7.32 (m, 2H), 7.21–7.13 (m, 2H), 6.85–6.36 (t, 1H, J=73.2 Hz), 4.41–4.37 (m, 1H), 3.82–3.76 (m, 2H), 3.34 (s, 3H), 2.47 (s, 3H), 1.62 (d, 3H, J=6.9 Hz). MS (AP) m/z 410.0 [(M+H)+, 100].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[SH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[OH-].[Na+]>CN(C)C=O>[NH2:8][C:7]1[C:6]2[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: COC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc(Br)cc2c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of 5-bromo-2-fluorobenzonitrile (13.5 g, 67.5 mmol) in N,N-dimethylformamide at 0° C. was added methyl 2-mercaptoacetate (6.45 mL, 70.88 mmol). The mixture was stirred at 0° C. for 30 minutes and 5N sodium hydroxide (20.25 mL) added. After stirring at 0° C. for 3 hours, the mixture was quenched with ice-water and the resulting precipitate collected by filtration and dried to give 18.5 g (96%) of a white solid. LCMS (APCI) m/z: 287(M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH:14][CH2:25][CH:24]=[CH2:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Product: C=CCNC[C@H](NC(=O)OCc1ccccc1)C(=O)OC

Procedure:
The β-amino functionality of Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine, methyl ester is then allylated with allyl trichloroacetimidate to give the corresponding Nα -(benzyloxycarbonyl)-β-(allylamino)-L-alanine, methyl ester using conditions described previously in Scheme F, step b.