Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH2:2]([O:6][CH:7]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([O:11]CC)=O)[CH2:3][CH2:4][CH3:5].[O-:31][C:32]#[N:33].[K+].Cl>C(O)C.O>[CH2:27]([O:26][CH:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:32](=[O:31])[NH:33][C:9]1=[O:11])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOC(OCCCC)C(NCCCCCCC(=O)OCC)C(=O)OCC
Reactant: N#C[O-]
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCOC(OCCCC)C1C(=O)NC(=O)N1CCCCCCC(=O)OCC
Temperature: 100 °C
Reaction time: 22 h
Yield: 107.8 %

Procedure:
A mixture of 2-(dibutoxymethyl)glycine ethyl ester (2.0 g) with ethyl 7-bromoheptanoate (1.82 g) was heated under nitrogen in a bath at 100° C. for 3 hours. to give crude ethyl 7-((2,2-dibutoxy-1-ethoxycarbonylethyl)amino)heptanoate hydrobromide. A stirred solution of 3.28 g of this hydrobromide in ethanol (13 ml) was cooled in ice-water and treated with a solution of potassium cyanate (1.34 g) in water (4 ml), followed by 2 N-aqueous hydrochloric acid (3.63 ml); the cooling bath was removed and stirring was continued at room temperature for 22 hours. The ethanol was evaported in vacuo, the residue was shaken with water and ether, and the ethereal solution was separated, washed with water and dried over magnesium sulphate (MgSO4); removal of the ether left an oil which was heated under nitrogen at 100° C. for 3 hours, to give 5-dibutoxymethyl-1-(6-ethoxycarbonylhexyl)hydantoin (2.94 g). This was stirred in ether (6 ml) with water (48 ml) and N-aqueous sodium hydroxide (24.9 ml) at room temperature for 11/2 hours and, after the addition of more ether (50 ml), the aqueous phase was separated, cooled (ice-H2O), stirred with fresh ether and acidified to Congo Red with N-aqueous hydrochloric acid. The ethereal solution of carboxylic acid was thrice washed with water, dried (MgSO4), and evaporated, to leave 1-(6-carboxyhexyl)5-dibutoxymethylhydantoin (2.15 g) as a gum. When 1.89 g of the latter were cooled in ice-water and stirred with concentrated aqueous hydrochloric acid (8.5 ml), the resulting solution gave place spontaneously to a suspension of colourless crystals. The suspension was set at room temperature for 11/2 hours, diluted with water (10 ml) and set aside for 15 minutes; the crystals were then collected, washed with water, dried in vacuo, suspended in ether (3 ml), and collected again, to give 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde (0.74 g), m.p. 223.5°-225° C. (Found: C. 51.86; H, 6.66; N, 10.62. C11H16N2O5 required, C, 51.56; H, 6.29; N, 10.93%). In dimethyl sulphoxide-d6, this compound exists predominantly as the masked aldehyde, 1-(6-carboxyhexyl)-5-hydroxymethylenehydantoin.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C:36]1[CH:37]=[C:38]([C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[CH:48][N:47]=[C:46]3[NH2:53])[CH:39]=[C:40]([F:42])[CH:41]=1>C(Cl)Cl>[NH2:53][C:46]1[C:45]2[C:50](=[CH:51][CH:52]=[C:43]([C:38]3[CH:37]=[C:36]([NH:35][C:8](=[O:10])[CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:41]=[C:40]([F:42])[CH:39]=3)[CH:44]=2)[N:49]=[CH:48][N:47]=1
Reactant: Nc1cc(F)cc(-c2ccc3ncnc(N)c3c2)c1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2ccc(-c3cc(F)cc(NC(=O)CN4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-morpholinoacetic acid (0.175 mmol, 25 mg) in a 4 mL vial was added HATU (0.175 mmol, 69 mg), 6-(3-amino-5-fluoro-phenyl)quinazolin-4-amine, 0.15 mmol, 38 mg), and TEA (0.30 mmol, 0.042 mL). The vial was capped and shaken overnight at room temperature. The reaction was then diluted with 3 mL DCM, then washed with 2 mL water. Organic phase was concentrated, and then purified by reverse phase HPLC yielding 20 mg of desired product. 1H NMR (400 MHz, DMSO) δ 10.07-9.93 (s, 1H), 8.60-8.52 (d, J=1.8 Hz, 1H), 8.42-8.39 (s, 1H), 8.08-8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.93-7.66 (m, 4H), 7.44-7.35 (d, J=10.0 Hz, 1H), 3.71-3.63 (m, 4H), 3.20-3.17 (s, 2H), 2.56-2.51 (m, 4H). LCMS M/Z (M+H) 382.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH2:10]COC)[N:7]2[NH:14][C:15](=[O:17])[N:16]=[C:6]2[C:5]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)[CH2:2][CH3:3].CC=C(C)C.B(Br)(Br)[Br:42]>C(Cl)(Cl)Cl>[CH2:1]([C:4]1[N:9]=[C:8]([CH2:10][Br:42])[N:7]2[NH:14][C:15](=[O:17])[N:16]=[C:6]2[C:5]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)[CH2:2][CH3:3]
Reactant: BrB(Br)Br
Reactant: CCCc1nc(CCOC)n2[nH]c(=O)nc2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC=C(C)C
Solvent: ClC(Cl)Cl
Product: CCCc1nc(CBr)n2[nH]c(=O)nc2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g of 7-n-propyl-5-methoxyethyl-8-{[2 '- (5-tetrazolyl)-4-biphenylyl]methyl}-1,2,4-triazolo[1,5-c]pyrimidin-2 (3H) -one, prepared in Example 169, are dissolved in 50 ml of chloroform stabilised with amylene. 0.7 ml of boron tribromide is added and the mixture is stirred for 8 hours at room temperature; the derivative 7-n-propyl-5-bromomethyl-8-{[2 '- (5-tetrazolyl ) -4-biphenylyl]methyl}-1,2,4-triazolo[1,5-c]pyrimidin-2(3H )-one thereby formed is taken up with dilute sodium hydroxide solution and stirred again for 6 hours. The aqueous phase is then separated after settling has taken place and acidified by bubbling in sulphur dioxide, and the crystals formed are drained, washed with acetone and then dried to give 0.6 g of 7-n-Propyl-5-hydroxymethyl-8-{[2'-(5 -tetrazolyl ) - 4 -biphenylyl ]methyl }- 1,2,4 -triazolo [ 1,5-c]pyrimidin-2(3H)-one in the form of crystals of melting point 182°-183° C.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][N:13]([CH3:26])[C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:16]=2[N:15]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>CCO>[CH3:1][N:2]([CH2:11][CH2:12][N:13]([CH3:26])[C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=2[N:15]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CCN(C)c1nc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)c1ccccc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(CCN(C)c1nc2cc(N)ccc2[nH]1)C(=O)c1ccccc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A mixture of N-methyl-N-[2-[methyl(5-nitro-1H-benzimidazol-2-yl)amino]ethyl]benzamide (1.30 g, 3.68 mmol) and SnCl2.2H2O (4.15 g, 18.39 mmol) in EtOH (15 mL) was heated under reflux for 1 hour. The mixture was cooled and made basic (pH8) with 2.5N NaOH. The precipitate was removed by filtration and the filtrate was concentrated. The residue was stirred with EtOAc (150 mL) overnight, dried (MgSO4), and concentrated to give 1.12 g (94%) of a green foam.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])=[O:7])[N:3]=[CH:2]1.[CH:22]([Mg]Cl)([CH3:24])[CH3:23].[Cl-].[NH4+]>C1COCC1.O>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:9]=[C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])([OH:7])[CH:22]([CH3:24])[CH3:23])[N:3]=[CH:2]1
Reactant: CC(C)[Mg]Cl
Reactant: COc1ccc(-c2ccccc2)cc1C(=O)c1c[nH]cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1C(O)(c1c[nH]cn1)C(C)C
Temperature: -40 °C
Reaction time: 1 h

Procedure:
1H-Imidazol-4-yl(4-methoxy[1,1′-biphenyl]-3-yl)methanone (0.62 g) was dissolved in THF (15 ml) and the mixture was cooled to −40° C. A solution (0.6 M; 15 ml) of isopropyl magnesium chloride in THF was slowly added dropwise and the mixture was warmed to room temperature. The mixture was stirred for 1 h and thereto was added saturated aqueous ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The extract was dried and concentrated. The obtained residue was purified by silica gel column chomatography (eluent, dichloromethane:methanol=40:1) to give the colorless amorphous title compound (0.16 g).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:28])=[C:9]([CH:27]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1)=[O:11])([CH3:4])[CH3:3].[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:28][C:35]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:36])=[C:9]([CH:27]=1)[C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)=[O:11])([CH3:1])[CH3:3]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: CC(C)(C)c1ccc(OC(=O)N2CCOCC2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 95 %

Procedure:
Using 5-[(1,1-dimethyl)ethyl]-2-hydroxy-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(O)(=O)C.[CH2:22]([CH2:24][NH2:25])[OH:23]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[NH:25][CH2:24][CH2:22][OH:23])=[CH:12]/[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(=O)c1ccc(OC)cc1OC
Reactant: NCCO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)/C=C(\NCCO)c1ccc(OC)cc1OC
Temperature: 83 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
To a mixture of methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (3.50 g, 14.69 mmol) and acetic acid (0.17 mL, 2.94 mmol) in i-PrOH (70 mL) was added ethanolamine (0.88 mL, 14.69 mmol) and the reaction mixture was heated to 83° C. Additional ethanolamine (0.88 mL, 14.69 mmol) was added to the reaction mixture at two, four and six hours. After stirring at 80° C. for 48 hours, the reaction mixture was cooled and concentrated under reduced pressure before the residue was suspended in equal parts of a saturated sodium bicarbonate solution and water under N2. After stirring overnight, the solids were collected by vacuum filtration and dried in a vacuum oven at 30° C. overnight to afford the title compound (2.72 g, 63%) as a beige colored power.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: COc1ccccc1N=C=O
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: COc1ccccc1NC(=O)Nc1ccc(-c2c(C(N)=O)[nH]c3cnccc23)cc1

Procedure:
25 mg of solid yellow 3-{4-[3-(2-methoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-methoxyphenyl isocyanate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])NCC3C=CC(Cl)=CC=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][CH:50]([CH3:52])[CH3:51])=[CH:45][CH:44]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])[N:49]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=3)[CH:50]([CH3:52])[CH3:51])[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NCc4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reactant: CC(C)Nc1ccc(Cl)cc1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)N(c4ccc(Cl)cc4)C(C)C)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was prepared as described for Compound 546c using Compound 546a in place of 4-chloro-N-methylaniline. MS: 595.27 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCO.[Pd]>[F:8][C:7]1[C:2]([F:1])=[C:3]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:4]=[CH:5][C:6]=1[NH2:9]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c(F)c1F
Reaction time: 5 h
Yield: 86.4 %

Procedure:
A mixture of 4-(2,3-difluoro-4-nitrophenyl)morpholine (11.5 g, 47 mmol) and 10% Pd—C (50% wet, 1.2 g) in EtOH (150 mL) was hydrogenated for 5 h at room temperature. The reaction mixture was filtered by celite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from iPr2O/AcOEt to give the title compound (8.7 g, 86% yield) as a pale red powder: NMR (300 MHz, DMSO-d6): δ ppm 2.77-2.95 (4H, m), 3.60-3.79 (4H, m), 5.07 (2H, s), 6.49 (1H, td, J=9.0, 1.9 Hz), 6.62 (1H, td, J=8.9, 2.3 Hz). LC-MS (ESI) ink 215 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[N:13]1([C:19]([S:21][CH3:22])=[S:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:16]1[CH2:17][CH2:18][N:13]([C:19]([S:21][CH3:22])=[S:20])[CH2:14][CH2:15]1
Reactant: CSC(=S)N1CCNCC1
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CSC(=S)N1CCN(Cc2ccccc2N(C)C)CC1
Yield: 42.7 %

Procedure:
In 20 ml of acetone, 2.06 g (10 mmol.) of 2-dimethylaminobenzyl chloride hydrochloride, 1.76 g (10 mmol.) of methyl piperazinecarbodithioate, and 1.06 g (10 mmol.) of sodium carbonate were stirred overnight at room temperature. Acetone was distilled off under reduced pressure. Water was added to the residue. The aqueous mixture was extracted with ether. The ether portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill of the solvent. The residue was purified by means of silica gel column and then recrystallized from ether to give 1.32 g of the desired compound as a white crystalline product, m.p. 90°-91° C., yield 42.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.Cl[CH2:28]/[C:29](/[CH3:54])=[CH:30]/[CH2:31][CH2:32][C:33]1([CH3:53])[CH2:38][CH2:37][C:36]2[CH:39]=[C:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:41]([CH3:44])=[C:42]([CH3:43])[C:35]=2[O:34]1.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:52][C:49]([Si:46]([CH3:47])([CH3:48])[O:45][C:40]1[C:41]([CH3:44])=[C:42]([CH3:43])[C:35]2[O:34][C:33]([CH2:32][CH2:31][CH:30]=[C:29]([CH3:28])[CH2:54][CH:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)([CH3:53])[CH2:38][CH2:37][C:36]=2[CH:39]=1)([CH3:50])[CH3:51]
Reactant: Cc1ccc(S(=O)(=O)Cc2cccc(C(F)(F)F)c2)cc1
Reactant: C/C(=C\CCC1(C)CCc2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1)CCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=CCCC1(C)CCc2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1)CC(c1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h

Procedure:
4-Methyl-1-[[[3-(trifluoromethyl)phenyl]methyl]sulfonyl]benzene (30 mmole) was dissolved in 100 mL of dry THF. The mixture was cooled to about -78° under nitrogen, and n-butyllithium (30 mmole) was added dropwise giving rise to a colored anion [yellowish-orange]. The solution was stirred for about 1 hour at about -78° before the addition of HMPA (5 mL) and [2-(5-chloro-4-methyl-3(E)-pentenyl)]-3,4-dihydro-6-[(1,1- dimethylethyl)dimethyl silyloxy]-2,7,8-trimethyl-2H-1-benzopyran (25 mmole). The mixture was stirred for about 1 hour at about -78°, then warmed to about -5° for about 12 hours, and poured into 1N HCl. The mixture was extracted with fresh ether. The combined organic fractions were washed With water and dried (brine, MgSO4). Concentration in vacuo gave a crude material that was purified by flash chromatography (gradient 10:1 to 2:1 hexanes:ether) to give the coupled product as colorless oil: IR (film) 2930, 1472, 1450, 1424, 1330, 1166, 1146, 1130, 1088 cm-1 ; 1H NMR (CDCl3) δ 0.16 (s, 6H), 1.00 (s, 9H), 1.09, 1.10 (s, 3H), 1.28 (m, 2H), 1.41, 1.39 (s, 3H), 1.60 (m, 2H), 1.91 (m, 2H), 2.02 (s, 3H), 2.07 (s, 3H), 2.39 (s, 3H), 2.56 (m, 2H), 2.74 (t, J=13.9 Hz, 1H), 3.09 (d, J=11.9 Hz, 1H), 4.22 (d of t, J=12.1, 4.0 Hz, 1H), 5.06 (m, 1H), 6.30 (s, 1H), 7.10 (s, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.36 (m, 4H), 7.48 (d, J=6.5 Hz, 1H); MS m/e 701 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:32][C:30]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH:31]=1
Reactant: NC(=O)c1ccc(Cl)cc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(Cl)ccc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4-chlorobenzamide (3.0 g, 17.6 mmol), 4-chloro-2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide was isolated as a yellow solid (0.650 g, 16% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.68 (d, J=4.03 Hz, 1 H), 7.23 (dd, J=8.51, 2.10 Hz, 1 H), 7.47 (d, J=8.23 Hz, 2 H), 7.79 (d, J=4.03 Hz, 1 H), 7.87 (d, J=8.42 Hz, 1 H), 7.91 (s, 1 H), 7.98 (d, J=8.42 Hz, 2 H), 8.41 (s, 1 H), 8.66 (d, J=2.20 Hz, 1 H), 12.65 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([F:22])([F:23])[C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A solution of (E)-4-(4,4,4-trifluoro-3-oxo-1-butenyl)phenoxyacetic acid, 1,1-dimethylethyl ester (1.578 g, 4.77 mmol) in dichloromethane (90 ml) was treated with trifluoroacetic acid (10 ml) and stirred at 22° C. for 4 h. The solvent and excess reagent were evaporated under reduced pressure and the last traces of trifluoroacetic acid were co-evaporated with toluene. Crystallization of the residue from ethyl acetate-hexane gave 1.29 g (98%) of the title material as white cubes: mp 156-156.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].[C:16]([O:19][CH2:20][C:21](Cl)=[O:22])(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:19][CH2:20][C:21]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:3]=1[C:4]#[N:5])=[O:22])(=[O:18])[CH3:17]
Reactant: N#Cc1c(N)cccc1N1CCOCC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1cccc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-morpholinobenzonitrile (5.6 g) in pyridine (15 ml) is added dropwise acetoxyacetyl chloride (3.3 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, pyridine is distilled off under reduced pressure and thereto is added water, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is recrystallized from ethanol-toluene-water to give the title compound (4.7 g) having the following physical properties.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.CCOC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:17]=[N+:18]=[N-:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCN=[N+]=[N-])CC1

Procedure:
To 1-4 (27.9 g, 0.082 moles) dissolved in DMSO (400 ml) was added sodium azide (5.61 g, 0.086 moles) at room temperature and the resulting solution was heated at 65° for 2 hrs. The cooled reaction mixture was diluted with 250 ml EtOAc, extracted with 2×100 ml portions of water, 2×50 ml portions of brine and then dried (MgSO4). Solvent removal provided 1-5 as a pale yellow oil, Rf 0.5 (silica gel, 20% acetone/hexane). ##STR13##
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([F:29])=[C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]3[CH2:22][CH2:21][C@:20]4([CH2:26][CH2:25][N:24]([CH3:27])[C:23]4=[O:28])[N:19]=3)[N:12]=2)[CH:10]=1)[CH3:3].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([F:29])=[C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([C@@H:18]3[CH2:22][CH2:21][C@:20]4([CH2:26][CH2:25][N:24]([CH3:27])[C:23]4=[O:28])[NH:19]3)[N:12]=2)[CH:10]=1)[CH3:3]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(C3=N[C@]4(CC3)CCN(C)C4=O)n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc(C)nc([C@@H]3CC[C@]4(CCN(C)C4=O)N3)n2)c1
Reaction time: 1.5 h
Yield: 28.7 %

Procedure:
Concentrated aq. HCl (75.18 μL, 0.88 mmol) was added to a solution of the (5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 20) (335 mg, 0.88 mmol) in DCM (20 mL) at 0° C. Finally, sodium triacetoxyborohydride (556.96 mg, 2.63 mmol) was added in a single portion and the resulting mixture was stirred for 90 mins. The reaction was quenched by the addition of sat. Na2CO3 and the resultant mixture was stirred for 5 mins. The phases were separated, the organic layer was dried (Na2SO4) and the solvent was evaporated to afford a brown oil. The material was purified using a Biotage SP4 with a 25 g SNAP cartridge, eluting with 0 to 20% MeOH/EtOAc over 20 column volumes. A partial separation was achieved. Faster running fractions were collected and evaporated to afford (2S,5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one as a light brown oil (97 mg)