Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.[CH3:14][OH:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:15][CH3:14]
Reactant: CO
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Product: COCc1cc(C(=O)OC)ccc1Br
Yield: 94 %

Procedure:
A solution of methyl 4-bromo-3-(bromomethyl)benzoate obtained in step 1 (37.50 g; 121.77 mmol) in MeOH (1 125 mL) was refluxed for 4 days. After concentration, the mixture was partitioned between EtOAc (500 mL) and water (200 mL). The organic layer was washed with a 5% NaHCO3 aqueous solution (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as a beige solid (29.8 g, 94%). 1H NMR (DMSO-d6) δ 8.06-8.05 (m, 1H), 7.83 (d, J=1.23 Hz, 2H), 4.54 (m, 2H), 3.90 (s, 3H), 3.45 (s, 3H). LC/MS (Method B): 227.2 (M−H)−. HPLC (Method A) Rt 4.42 min (Purity: 93.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[Cl:18][C:9]1[N:8]=[C:7]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C1CCNCC1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(Cl)nc(N3CCCCC3)c2c1
Reaction time: 2 h

Procedure:
To 367 mg (1.77 mmol) of 6-nitroquinazoline-2,4 (1H,3H)-dione was added 15.13 g (98.70 mmol) of phosphorus oxychloride to effect reaction in the same manner as in Example 10. Next, to the reaction mixture was added dropwise 301 mg (3.54 mmol) of piperidine under ice cooling, and the resulting mixture was stirred under ice cooling for 2 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered out to obtain 2-chloro-6-nitro-4-piperidinoquinazoline. The compound was dissolved in 1 ml of DMF, and after 1.52 g (26.65 mmol) of allylamine was added to the resulting solution, the resulting mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 213 mg (yield: 38.4%) of the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[CH:17][C:7]2[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1.Cl[C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[CH2:21]1.C(=O)([O-])O.[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[F:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:24][C@H:23]3[CH2:25][CH2:20][CH2:21][N:22]3[CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:32][CH:33]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1
Reactant: Fc1ccc2c(c1)COc1ccccc1N2
Reactant: Cl[C@@H]1CCCN(CCc2ccc(N3CCCC3)cc2)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: Fc1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCN1CCc1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (348 mg, 8.7 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (50 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 2-Fluoro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (1.70 g, 7.90 mmol) was added to the suspension, and they were.stirred at room temperature for 30 minutes and then at 50° C. for additional 30 minutes. A solution of (R)-3-chloro-1-(4-pyrrolidinophenethyl)piperidine (2.64 g, 9.02 mmol) in dimethyl sulfoxide (25 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction mixture was distributed into saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (6:1) and then with hexane and ethyl acetate (1:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-2-fluoro-5,11-dihydro-5-[1-(4-pyrrolidinophenethyl)pyrrolidin-2-ylmethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (2.29 g, 68%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>CN(C=O)C>[CH3:25][O:26][C:27](=[O:37])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:7]3[C:6]4[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[N:9][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=2)=[CH:33][CH:34]=1
Reactant: Cc1cccc2c(-c3cccc(N)c3)c(-c3ccccc3)nnc12
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(C)cccc34)c2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
3-(8-Methyl-3-phenyl-cinnolin-4-yl)-phenylamine (0.031 g, 0.1 mmol) and (4-formyl-phenyl)-acetic acid methyl ester (0.07 g, 0.4 mmol) were mixed in DMF (4 mL) and then treated with NaBH(OAc)3 (0.43 g, 2.0 mml) and acetic acid (0.4 mL). After stirring at 40° C. for 4 hours the mixture was quenched with water and then extracted with ethyl acetate. The organic residue was purified by silica gel chromatography using 5-50% EtOAc/hexanes as eluent to provide (4-{[3-(8-methyl-3-phenyl-cinnolin-4-yl)-phenylamino]-methyl}-phenyl)-acetic acid methyl ester as a gum which was used for the next reaction. MS (EI) m/z 474;
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[ClH:9].[CH3:10][NH:11][CH3:12].[CH2:13]=O.Cl>C(O)C>[ClH:9].[CH3:10][N:11]([CH2:13][CH2:2][C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:3])[CH3:12]
Reactant: CNC
Reactant: CC(=O)c1ccco1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccco1
Yield: 13 %

Procedure:
2-Acetylfuran (13.8 g), dimethylamine hydrochloride (13.3 g), paraformaldehyde (5.0 g) and ethanol (80 ml) acidified with concentrated HCl (1.0 ml) were stirred. Part of this mixture (27 ml) was pumped through the CMR (18 ml/min; 160°-70° C.; 500 kPa;) and the hot product collected in an ice-water cooled flask, to afford pale yellow crystals m.p. 172.5°-173° C. (cf lit.10 m.p. 173°-4° C.) in 13% yield.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: COc1ccccc1CCNS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (1.0 M in CH2Cl2, 80.8 mL, 80.8 mmol) was added to a solution of N-[2-(2-methoxy-phenyl)-ethyl]-methanesulfonamide (18.5 g, 80.8 mmol) in CH2Cl2 (200 mL). The reaction was stirred at room temperature for 2 h and was poured onto water (200 mL). The aqueous layer was extracted with CH2Cl2 (2×) and the organic solution was washed with water (1×) and aqueous NaHCO3 (satd, 1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford N-[2-(2-hydroxy-phenyl)-ethyl]-methanesulfonamide (16.8 9). 1H NMR (400 MHz, CDCl3) δ 7.11 (m, 2H), 6.86 (m, 1H), 6.80 (m, 1H), 4.79 (m, 1H), 3.39 (t, 2H), 2.88 (t, 2H), 2.77 (s, 3H).
Reaction SMILES: [C:1]12([PH:11][C:12]34[CH2:21][CH:16]5[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]5)[CH2:13]3)[CH2:19]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC=CC=1.C(Br)CCC>C(OCCCC)CCC>[C:1]12([P:11]([C:12]34[CH2:19][CH:18]5[CH2:20][CH:14]([CH2:15][CH:16]([CH2:17]5)[CH2:21]3)[CH2:13]4)[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: [Li]CCCC
Reactant: C1C2CC3CC1CC(PC14CC5CC(CC(C5)C1)C4)(C2)C3
Solvent: Cc1ccccc1
Solvent: CCCCBr
Solvent: CCCCOCCCC
Product: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2

Procedure:
4.6 g (15 mmol) of di(1-adamantyl)phosphine were placed in 50 ml of di-n-butyl ether, and 20 ml of a 2.5 M solution of n-BuLi in toluene (50 mmol) were added. The mixture was refluxed for 1 h and cooled and 4.1 g (30 mmol) of 1-butyl bromide were added dropwise. The mixture was refluxed for 30 min, cooled and washed with saturated ammonium chloride solution (3×), the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[OH-].[NH4+:14]>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH2:14])(=[O:11])=[O:10]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of 60.0 g of 2,3-dichlorobenzenesulfonyl chloride in 500 mL of tetrahydrofuran at 0° C. was added 30 mL of concentrated ammonium hydroxide (30%) dropwise at a rate that maintained the temperature below 15° C. After an additional stirring period of 0.5 hr, the tetrahydrofuran was evaporated under reduced pressure. The resultant solid residue was triturated with 500 mL of water, filtered, and the collected solid washed twice with 100-mL portions of water and dried to yield 52 g of 2,3-dichlorobenzenesulfonamide as a tan solid, m.p. 210°-226° C.; IR (nujol): 3360, 3250, 1370, 1175, 1165 cm-1.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.CCN=C=NCCCN(C)C.[OH:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH:35]3[CH2:42][C:43](O)=[O:44])[CH2:33]1)[CH2:39]2>C(Cl)Cl>[OH:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH:35]3[CH2:42][C:43]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:44])[CH2:33]1)[CH2:39]2
Reactant: O=C(O)CC1C2CC3CC1CC(O)(C3)C2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC1CC(O)(C4)C3)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Triethylamine 0.38 ml was added to a methylene chloride 15 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.44 g, and stirred at 0° C. for 30 min. WSC 0.53 g and 5-hydroxy-2-adamantyl acetic acid 0.44 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 14.5 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(5-hydroxy-2-adamantyl acetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 95.5 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then added water, and removed the insoluble material by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: methanol=150:1) to obtain the product. Yield: 556 mg (Yield 79%)
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.CC#N.O>O1CCCC1>[CH2:25]([C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:6][O:7][C:8]=2[CH:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccccc5)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccccc5)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(S)-6-[(R)-4-Benzyl-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester (18.6 mg) is dissolved in tetrahydrofuran (4 mL) and 1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture is stirred at room temperature overnight and then acidified with 1N aqueous hydrochloric acid (0.4 mL). The solution is submitted to HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=0.72 min; Mass spectrum (ESI−): m/z=417 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=C([CH:7]=[C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:9]=1)C#N.[OH-:17].[Na+].Cl.[CH2:20]([OH:22])[CH3:21]>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:21]([CH:7]=[C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:9]=1)[C:20]([OH:17])=[O:22]
Reactant: CCO
Reactant: N#Cc1cc(F)cc(Oc2cncnc2)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cc(F)cc(Oc2cncnc2)c1
Yield: 99 %

Procedure:
Compound 4 (1.36 g, 6.32 mmol, 1.00 eq) was dissolved in ethanol (32 mL) and 1N NaOH (17 mL) was added. The mixture was refluxed for 18 h and after cooling the reaction was neutralized with 1N HCl (11 mL) and the reaction was concentrated in vacuo. The crude reaction was dissolved in 10% MeOH/CH2Cl2 and the undissolved salt was filtered off and the solvents were removed in vacuo to afford 1.47 g (99%) of the title compound as a pale-yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.72 (s, 2H), 7.44 (ddd, J=9.2, 2.4, 1.1 Hz, 1H), 7.34-7.32 (m, 1H), 7.22 (dt, J=9.5, 2.4 Hz, 1H); [M+1]+: 235.1
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9](=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.C(O)C.[H][H]>[Ni].O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9](=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(=O)C=Cc1ccc(C)o1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCC(=O)CCc1ccc(C)o1
Temperature: 70 °C

Procedure:
For the hydrogenation reaction, 10 g of ethyl 6-(5-methylfuran-2-yl)-4-oxohex-5-enoate, 1 g of 10% wet weight basis Raney Nickel, 100 mL of ethanol, and 5 mL of water were combined in a Parr Bottle. The mixture was pressurized to 50 psi with hydrogen gas and heated to 70° C. The mixture was stirred until hydrogen uptake stopped. The mixture was cooled to ambient temperature, filtered, and washed with ethanol. The filtrate was rotary evaporated to yield ethyl 6-(5-methylfuran-2-yl)-4-oxohexanoate. The ethyl 6-(5-methylfuran-2-yl)-4-oxohexanoate (9.9 g) was then dissolved in hexanes solvent (Aldrich) and dried with sodium sulfate. The solids were filtered, and washed with hexanes. The hexane was combined with the liquid extract and evaporated to an oil. The oil was dissolved in 100 mL isopropyl alcohol (IPA) and added to a Parr bottle containing IPA-washed Raney Nickel (5.0 g wet weight). The reaction mixture was pressurized to 50 psi with hydrogen gas and heated to 70° C. The reaction mixture was stirred until hydrogen uptake stopped. The Raney Nickel was filtered off and washed with IPA. The IPA was then combined with the liquid extract and evaporated to produce ethyl 4-hydroxy-6-(5-methyltetrahydrofuran-2-yl)hexanoate.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[C:16]([O:20][C:21](=[O:24])[CH2:22][NH:23][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
N-Carbobenzyloxy-glycine (2.1 g, 10 mmol) and glycine-tert-butyl ester (1.3 g, 10 mmol) were coupled using benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (4.4 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in acetonitrile following the method described in Example 23 to give 2.5 g(79%) of N-carbobenzyloxy-glycylglycine-tert-butyl ester after chromatography on silica gel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:14]/[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)/[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[C:37]1(/[CH:43]=[CH:44]/C2C=CC(B(O)O)=CC=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:26][C:25]=1[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15]/[N:14]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2](/[CH:44]=[CH:43]/[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:7][CH:6]=2)\[C:9]([OH:11])=[O:10])=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(/C=C/c2ccccc2)cc1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2ccc(/C=C/c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A mixture of ethyl Z-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (830 mg), 4(E-2-phenylethenyl)phenylboronic acid (268 mg), potassium carbonate (626 mg), toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under an argon atmosphere for 30 minutes at room temperature. Tetrakis (triphenylphosphine)palladium (0) (105 mg) was added and the mixture was heated under reflux for 14 hours. The reaction mixture was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residues were subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred for 2 hours at 40° C. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[4-(E-2-phenylethenyl)phenyl]acetic acid (634 mg, yield: 77%) as pale-yellow crystals. m.p. 194-195° C. (decomposition)
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([C:20]2[N:21]=[C:22]([NH:30][C:31]3[C:36]([C:37](O)=[O:38])=[CH:35][N:34]=[CH:33][CH:32]=3)[C:23]3[CH:29]=[CH:28][CH:27]=[N:26][C:24]=3[N:25]=2)[CH:19]=1.[CH3:41][NH2:42]>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:42][CH3:41])=[C:18]([C:20]2[N:21]=[C:22]([NH:30][C:31]3[C:36]([C:37]([NH:3][CH3:1])=[O:38])=[CH:35][N:34]=[CH:33][CH:32]=3)[C:23]3[CH:29]=[CH:28][CH:27]=[N:26][C:24]=3[N:25]=2)[CH:19]=1
Reactant: CN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2ncccc12
Solvent: CN(C)C=O
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2NC)nc2ncccc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
Carbonyldiimidazole (180 mg, 1.11 mmol) was added to a stirred suspension of the acid, 4-[2-(5-Chloro-2-fluoro-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-nicotinic acid (240 mg, 0.56 mmol) in dry DMF (15 ml). The reaction was heated to 60° C. for 2 hours under nitrogen. The reaction was cooled to room temperature and MeNH2 (2M in THF, 5 equivalents) was added and the reaction stirred for 18 hours. The reaction mixture was partitioned between CHCl3 (50 mL) and water (50 mL). The organic layer was further washed with water (3×50 mL). The product precipitated out of the CHCl3 solution and was filter to give compound 4-[2-(5-Chloro-2-methylamino-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-N-methyl-nicotinamide (47 mg, 19% yield).
Reaction SMILES: C([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=C(C#N)[C:7]=2[CH:6]=[CH:5]1)(=O)C.[OH-:15].[Na+].[CH2:17]([OH:19])[CH3:18].Cl>O>[NH:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:18]([C:17]([OH:15])=[O:19])[C:7]=2[CH:6]=[CH:5]1
Reactant: CC(=O)n1ccc2c(C#N)ccnc21
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccnc2[nH]ccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A mixture of 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (1.80 g, 11.10 mmol), 2 M aqueous sodium hydroxide solution (25 mL) and ethanol (25 mL) was stirred at 90° C. for 16 hr. The reaction mixture was neutralized with hydrochloric acid and diluted with water. The precipitate was collected by filtration, and washed with water and diethyl ether to give the title compound (1.51 g, yield 84%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.CC[N:13]([CH:17]([CH3:19])[CH3:18])C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)CC1>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:13][CH:17]2[CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Product: O=C(NC1CC1)c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
2-Chloropyrimidine-4-carboxylic acid (0.516 g, 3.25 mmol) (Maybridge Chemicals, Maybridge, UK), DIPEA (0.94 mL, 5.42 mmol) and PyBop (1.69 g, 3.25 mmol) were weighed into a 150 mL RBF and dissolved in dioxane (15 mL). The solution was stirred at RT, then cooled to 0° C., and stirred for 5 min. Cyclopropylamine (0.38 mL, 5.42 mmol) was added, and the solution was stirred at 0° C. for 1 h. The mixture became solid. Additional dioxane was added (6 mL), the flask was removed from the ice bath and the contents were stirred at RT for 68 h. EtOAc was added and the mixture was washed with water (75 mL), 1 N NaOH (75 mL) and brine (75 mL). The crude material was purified by flash chromatography using an ISCO Combiflash Rf(25 g Thomson Single Step silica gel column; 20-100% EtOAc in hexanes) to afford 2-chloro-N-cyclopropylpyrimidine-4-carboxamide (0.139 g, 0.703 mmol, 25.9% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 197.9 (M+H)+.