Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:9][CH:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[CH2:4]1.[C:11]1([S-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:11]1([S:17][CH2:2][CH:3]2[O:9][CH:8]3[N:5]([C:6](=[O:10])[CH2:7]3)[CH2:4]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CC2OC(CBr)CN12
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC2OC(CSc3ccccc3)CN12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
(3RS, 5SR)-3-Bromomethyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (210 mg, 1.0 mmole) in dry dimethylformamide (2 ml) was added dropwise to a stirred solution of sodium thiophenolate (1.2 mmole) in dry DMF (5 ml). The solution was stirred at room temperature with exclusion of moisture for 16 hours and was then diluted with ethyl acetate (30 ml). The solution was washed three times with water, dried, and the solvent removed to give a colourless oil. The oil was chromatographed on silica gel (15 g) using ethyl acetate/petroleum ether to give the title compound as a colourless gum (205 mg, 87%). (Found : M+, 235.06551. C12H13NO2S requires 235.06669. νmax (CHCl3) 1785 (β-lactam C=O)cm-1 δ p.p.m. (CDCl3) 2.6 - 3.5 [complex, 5H, C(6)H2, C(2)H, CH2SPh[; 4.10 [dd, J 11.5Hz, J' 6Hz, 1H, C(2)H]; 4.52 [quin., J 6Hz, 1H, C(3)H]; 5.43 [d, J 2.5Hz, 1H, C(5)H]; 7.48 (5H, aromatic H). m/e : 235 (M+, 100%), 192 (30), 123 (71).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39](=[O:53])[NH:40][CH2:41][CH2:42][C@H:43]([NH2:52])[C:44]([N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:45])([CH3:37])([CH3:36])[CH3:35].[C:54]([O:58][C:59](=[O:81])[C:60]1[CH:65]=[C:64]([C:66]2[CH:71]=[C:70]([S:72][CH2:73][CH2:74][C:75](O)=[O:76])[N:69]=[C:68]([NH2:78])[N:67]=2)[C:63]([CH3:79])=[CH:62][C:61]=1[CH3:80])([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[C:54]([O:58][C:59](=[O:81])[C:60]1[CH:65]=[C:64]([C:66]2[CH:71]=[C:70]([S:72][CH2:73][CH2:74][C:75](=[O:76])[NH:52][C@H:43]([C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[O:45])[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:53])[N:69]=[C:68]([NH2:78])[N:67]=2)[C:63]([CH3:79])=[CH:62][C:61]=1[CH3:80])([CH3:57])([CH3:56])[CH3:55]
Reactant: Cc1cc(C)c(-c2cc(SCCC(=O)O)nc(N)n2)cc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC[C@H](N)C(=O)N1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-c2cc(SCCC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)N3CCOCC3)nc(N)n2)cc1C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (58 mg, 0.149 mmol), and diisopropylethylamine (43 μl, 0.247 mmol) were added at room temperature to an N,N-dimethylformamide solution (1.0 ml) of ((S)-3-amino-4-morpholin-4-yl-4-oxobutyl)carbamic acid tert-butyl ester (44 mg) obtained in Step 2 above and 5-[2-amino-6-(2-carboxyethylsulfanyl)pyrimidin-4-yl]-2,4-dimethyl-benzoic acid tert-butyl ester (50.3 mg) obtained in Step 1 of Example 2-1. The reaction solution was stirred for 16 hours, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=30:1) to yield 5-(2-amino-6-{2-[(S)-3-tert-butoxycarbonylamino-1-(morpholine-4-carbonyl)propylcarbamoyl]ethylsulfanyl}pyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (84 mg) as a pale yellow oily material.
Reaction SMILES: OS([O-])=O.[Na+].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[NH2:25])[C:18]([O:20][CH3:21])=[O:19].O>C(O)C>[C:7]1([C:6]2[NH:25][C:24]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2[nH]c(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
An aqueous solution of NaHSO3 (21.0 mL, 40% in water) was treated benzaldehyde (2.00 mL, 20.0 mmol) and stirred at ambient temperature for 1 h. A solution of methyl 3,4-diaminobenzoate (3.32 g, 20.0 mmol) in ethanol (15.0 mL) was added and the solution was heated to reflux for 6 h. Upon cooling, the solution was poured into water and the resultant precipitate was collected by filtration, washed with water, and dried in vacuo to provide the title compound as a grey solid (4.90 g; 97%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.85 (br. s., 1H) 8.35 (s, 1H) 8.11 (d, J=2.0 Hz, 1H) 8.10 (d, J=4.0 Hz, 1H) 7.97 (dd, J=8.6, 1.5 Hz, 1H) 7.63 (d, J=5.8 Hz, 1H) 7.46 (d, J=2.3 Hz, 2H) 7.45 (dd, J=5.5, 4.0 Hz, 1H) 3.94 (s, 3H). MS (ES+) m/e 253 [M+H]+.
Reaction SMILES: NC1N=C(N)C2C=C(C=C(C3C=CC(C(O)=O)=CC=3)C)C=NC=2N=1.[NH2:25][C:26]1[N:27]=[C:28]([OH:48])[C:29]2[CH:35]=[C:34]([CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][CH:40]=3)C)[CH:33]=[N:32][C:30]=2[N:31]=1>>[NH2:25][C:26]1[N:27]=[C:28]([OH:48])[C:29]2[CH:35]=[C:34]([CH:36]=[CH:37][C:39]3[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][CH:40]=3)[CH:33]=[N:32][C:30]=2[N:31]=1
Reactant: CC(=Cc1cnc2nc(N)nc(O)c2c1)c1ccc(C(=O)O)cc1
Agent: CC(=Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)O)cc1
Product: Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1

Procedure:
In a similar fashion, 2,4-diamino-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine is converted to 2-amino-4-hydroxy-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine, mp>250° C.; NMR (DMSO-d6, 80 MHz) d 2.28 and 2.30(brs, 3H), 6.77 and 7.06(brs, 1H), 7.72(d, 2H, J=8.5 Hz), 7.97(d, 2H, J=8.5 Hz), 8.27(d, 1H, J=2.0 Hz), 8.72(d, 1H, J=2.0 Hz).
Reaction SMILES: CC([O:5][C:6](=[O:50])[C@H:7]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:49])[NH2:48])[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([NH:27][C@H:28]([C:36]([O:38]C(C)(C)C)=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:10])(C)C>ClCCl.FC(F)(F)C(O)=O>[C:11]1([C:9]([NH:8][C@H:7]([C:6]([OH:50])=[O:5])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:48])[NH2:49])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@H](CCCNC(=N)N)NC(=O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CCCNC(=N)N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NCCC[C@H](NC(=O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)C(=O)O
Yield: 59.8 %

Procedure:
This compound was prepared according to the general method of Example 122 using N,N'-[Dithiobis (2,1-phenylenecarbonyl)bis-L-arginine-bis(1,1-dimethylethyl) ester, (1.31 g, 2.0 mmol) from Example 127 in 15 mL of dichloromethane and 15 mL of trifluoroacetic acid. The residue was triturated with ethanol and 1N HCl to yield 0.74 g of the title compound, mp 208-211° C.;
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:26])=[C:22]([CH3:25])[CH:23]=2)[N:18]([CH3:27])[C:17](=[O:28])[C:16]=1C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[NH2:3][C:16]1[C:17](=[O:28])[N:18]([CH3:27])[C:19]2[C:24]([C:15]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8])=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2
Reactant: CCN(CC)CC
Reactant: Cc1cc2c(-c3ccccc3Cl)c(C(=O)O)c(=O)n(C)c2cc1C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cc2c(-c3ccccc3Cl)c(N)c(=O)n(C)c2cc1C
Yield: 69.2 %

Procedure:
Triethylamine (0.7 ml) was added dropwise to a mixture of 4-(2-chlorophenyl)-1,2-dihydro-1,6,7-trimethyl-2-oxo-3-quinolinecarboxylic acid (1.71 g), diphenylphosphoryl azide (1.65 g) and benzene (25 ml) under stirring. The mixture was further stirred for 15 minutes at room temperature and for 30 minutes under reflux, and then distilled to remove the solvent. The residue was dissolved in a mixture of dioxane (20 ml) and 1sodium hydroxide (7.5 ml) , followed by refluxing for 15 minutes. The resulting solution was acidified with 2N hydrochloric acid and then stirred for 20 minutes at room temperature. The mixture was made alkaline with 2N sodium hydroxide. The resultant crystals were collected by filtration to give 3-amino-4-(2-chlorophenyl)-1,6,7-trimethyl-2(1H)-quinolone (1.08 g, 69.2%), which was recrystallized from a mixture of chloroform and ethanol to give colorless needles. mp 242°-243° C.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C25H25ClN6O2, 479.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14][CH:15](O)[CH:16]=[CH2:17].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:14]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH:15]=[CH:16][CH3:17]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1CCc2cc(OC)ccc2C1=O
Reaction time: 50 h
Yield: 57 %

Procedure:
3,4-dihydro-6-methoxy-1(2H)-naphthalenone (198 g) was dissolved in 2000 ml of toluene under argon and treated in succession with 193 ml of 3-buten-2-ol, 206 ml of 2,2-dimethoxypropane and 1.9 g of p-toluenesulphonic acid. The reaction mixture was boiled at reflux for 20 hours, treated with a further 175 ml of 3-buten-2-ol and 180 ml of 2,2-dimethoxypropane and boiled for a further 50 hours. After cooling the solution was washed with 500 ml of saturated sodium hydrogen carbonate solution, the aqueous phase was extracted once with 600 ml of ethyl acetate, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 269 g of brown oil, was chromatographed on 3000 g of silica gel with hexane/diethyl ether (5:1) as the eluent. There were obtained 147 g (57%) of 2-(2-butenyl)-3,4-dihydro-6-methoxy-1(2H)-naphthalenone which was processed without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:8]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[CH3:1][C:2]1[CH:21]=[CH:20][C:5]([N:6]2[CH:24]=[CH:22][CH:8]=[C:7]2[C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: Cc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1
Product: Cc1ccc(-n2cccc2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methylanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a pale brown powder (yield 28%), melting at 131-134° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][NH2:15])=O)(=[O:4])=[O:3].[OH-].[K+].[C:18](=[S:20])=[S:19]>C(O)C.O>[SH:20][C:18]1[S:19][C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([NH2:1])(=[O:4])=[O:3])=[N:14][N:15]=1
Reactant: NNC(=O)Cc1ccccc1S(N)(=O)=O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1Cc1nnc(S)s1

Procedure:
To a suspension of 22 g of the hydrazide prepared in Example 1 in 175 ml of absolute ethanol was added a solution of 5.4 g of potassium hydroxide in 40 ml of water. After stirring several minutes, 9.2 g of carbon disulfide was added dropwise. The suspension was refluxed 4 hours then concentrated in vacuo. After water (about 200 ml) was added to the residue and the suspension stirred several minutes, the suspension was filtered, and the filtrate was acidified with concentrated hydrochloric acid (red to litmus paper). The mixture was filtered and the solid isolated was suction-dried to give 5 g of the crude subject compound; m.p. 173°-197° C.
Reaction SMILES: FC(F)(F)C(N1C[C@H](C)C2C=C(Cl)C=CC=2CC1)=O.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]([CH3:31])[C:25]=2[C:32]=1[Cl:33]>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]([CH3:31])[C:25]=2[C:32]=1[Cl:33]
Reactant: C[C@@H]1CNCCc2ccc(Cl)c(Cl)c21
Agent: C[C@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Product: C[C@H]1CNCCc2ccc(Cl)c(Cl)c21

Procedure:
Compound 7 was prepared from (R)—N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizing a similar two step procedure as described herein for the preparation of Compound 5. 1H NMR (400 MHz, CDCl3) δ 7:40 (d, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 4.17 (m, 1H), 3.55 (m, 2H), 3.5-3.3 (m, 2H), 3.2-3.0 (m, 2H), 1.43 (d, J=7 Hz, 3H). MS calculated for C11H13Cl2N+H: 230, observed: 230.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[N:10]1([C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:27])[F:28])=[CH:23][CH:22]=3)[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1cc(Cl)nc(N2CCCC2)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
A solution of nitrile 25A (2.58 g, 12.5 mmol) in DME (90 mL) was added with 4-trifluoromethoxy phenyl boronic acid (2.64 g, 1.0 mol eq,) and NaHCO3 (3.15 g, 3 mol eq,) suspended in water (45 mL). The mixture was degassed under vacuum, then Palladium Tetrakis was added (catalytic amount) and the reaction was stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (80 mL). The aqueous phase was extracted with EtOAc (3×60 mL) and the combined organic layer was washed with brine (80 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to afford 26C as deliquescent yellow solid (3.2 g, 9.6 mmol, 77% Yield). 1HNMR (DMSO, 400 MHz) δ 1.85 (m, 4H), 3.42 (m, 4H), 6.38 (s, 1H), 7.08 (s, 1H), 7.38 (d, 2H, J=8), 8.05 (d, 2H, J=8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[NH:11][C:10]=2[CH3:22])=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[N:11]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])[C:10]=2[CH3:22])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Reactant: CC(C)(C)OC(=O)CBr
Product: COC(=O)c1ccc2c(c1)c(Sc1ccc(Cl)cc1)c(C)n2CC(=O)OC(C)(C)C

Procedure:
The sub-title compound was prepared by the method of example 11 part (ii) using the product of part (ii) and t-butylbromoacetate. The product was purified using flash column chromatography (14% EtOAc/hexane as eluent).
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[C@H:6]([CH3:19])[CH2:5]1.C(OC([N:27]([CH2:40][CH:41]1[CH2:43][CH2:42]1)[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C@@H:29]([CH2:28][NH:27][CH2:40][CH:41]2[CH2:43][CH2:42]2)[C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:12]3[C:7]4[C@H:6]([CH3:19])[CH2:5][C@@H:4]([F:3])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:18][CH2:17]2)=[O:31])=[CH:38][CH:37]=1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@H](CNCC4CC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5R,7R)-7-Fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.535 g, 1.730 mmol) and (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chloropheny)propanoic acid (0.6122 g, 1.730 mmol) were combined in methylene chloride (15 mL) and treated with diisopropylethylamine (0.9041 ml, 5.191 mmol). HBTU (0.6579 g, 1.730 mmol) was then added. The reaction was stirred at ambient temperature for 16 hours. ESI MS looked excellent for desired product. The reaction was quenched with 10% Na2CO3, diluted with methylene chloride and separated. The aqueous portion was washed with methylene chloride (2×), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The material was applied to a 40 mm samplet and air-dried. This was placed on top of a column (Biotage 40S) and eluted with 3:2 hexane/EtOAc. The major spot was collected to give tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate as a white solid (955 mg, 96%). LC/MS (APCI+) m/z 571.9 [M+H]+
Reaction SMILES: [CH3:1][O: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][N:14]([C:18]([CH3:20])=[O:19])C(=O)C.[B-](F)(F)(F)F.[CH3:26][CH2:27][O+:28](CC)CC>ClCCl.CO>[C:27]([C:7]1[NH:8][C:9]2[C:5]([C:6]=1[CH2:12][CH2:13][NH:14][C:18](=[O:19])[CH3:20])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)(=[O:28])[CH3:26]
Reactant: CC[O+](CC)CC
Reactant: COc1ccc2[nH]cc(CCN(C(C)=O)C(C)=O)c2c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c(C(C)=O)c(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To N-[2-(5-methoxyindol-3-yl)ethyl]diacetamide (4) (35 mg) dissolved in dichloromethane (3 ml), at 0° C., is added Meerwein's reagent (0.15 mmol, 0.15 ml). The mixture is maintained at room temperature for 12 h. The solution is filtered. A red precipitate is obtained. The precipitate is dissolved in methanol (1 ml). After reacting for 15 min, the methanol is evaporated off and the ethyl acetate is extracted out. N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide (2) is thus obtained, Yield=75%.
Reaction SMILES: C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:35](#[N:39])[CH2:36][C:37]#[N:38]>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([CH:36]([C:35]#[N:39])[C:37]#[N:38])=[O:32])=[CH:33][CH:34]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#CCC#N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC(C#N)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
Diethylcyanophosphonate (5 mmol) and triethylamine (15 mmol) are added to a solution of 4-benzyloxybenzoic acid (18, 5 mmol) and malononitrile (4.8 mmol) in DMF (10 mL) stirred at 0° C. After the addition is complete, stirring is continued as the solution is allowed to warm to ambient temperature. Progress of the reaction is followed by tic and when complete, the reaction solution is concentrated under reduced pressure. The residue is taken up in EtOAc and washed with cold 1N HCl and then with aq. NaHCO3. The alkaline bicarbonate wash is acidified with 6N HCl and the mixture is extracted with EtOAc. The combined EtOAc extract solutions are dried (Na2SO4), filtered and concentrated under reduced pressure, giving the desired 4-benzyloxybenzoylmalononitrile 19. The product is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[ClH:17].O>C(Cl)(Cl)(Cl)Cl.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([Cl:17])([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: C=C(C)COc1cc(OCC#CC)ncn1
Reactant: Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC#CCOc1cc(OCC(C)(C)Cl)ncn1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
In 1.2 ml of carbon tetrachloride were dissolved 0.15 g of 4-(2-butynyloxy)-6-(2-methylallyloxy)pyrimidine and 0.01 g of trioctylmethylammonium chloride, to which 1 ml of concentrated hydrochloric acid was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 50 minutes. The reaction mixture was then poured into water, which was extracted three times with t-butyl methyl ether. The combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.08 g of 4-(2-butynyloxy)-6-(2-chloro-2-methylpropyloxy)pyrimidine (the present compound (20)).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[C:6]([O:10][C:11]([NH:13][N:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(OCC)(=O)C>[C:6]([O:10][C:11]([NH:13][N:14]1[CH2:18][CH2:17][N:16]([Si:2]([CH3:4])([CH3:3])[CH3:1])[C:15]1=[O:19])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NN1CCNC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN1CCN([Si](C)(C)C)C1=O
Reaction time: 8 h
Yield: 91.1 %

Procedure:
While cooling, 10.55 g (97.1 mmol) of trimethylsilylchloride was dropped into a solution of 19.55 g (97.1 mmol) of 1-[(t-butoxycarbonyl)amino]-2-imidazolidinone and 9.83 g (97.1 mmol) of triethylamine in 900 ml of absolute ethyl acetate. After stirring overnight, the salt was filtered off and the filtrate evaporated in vacuo to yield 24.18 g of 1-[(t-butoxycarbonyl)amino]-3-(trimethylsilyl)-2-imidazolidinone, melting point 132.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15]([OH:17])C.C=O.C1CCN2C(=NCCC2)CC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH:12]([CH2:15][OH:17])[C:13]#[N:14]
Reactant: N#CCc1cc(OC(F)F)ccc1Cl
Reactant: CCO
Agent: C=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: N#CC(CO)c1cc(OC(F)F)ccc1Cl
Reaction time: 0.83 h
Yield: 65 %

Procedure:
A 25 mL flask with a stir bar was charged with 3.0 g (13.8 mmol) of 2-(2-chloro-5-(difluoromethoxy)phenyl)ethanenitrile, 12 mL of ethanol and 1.34 mL of 37% formaldehyde solution. The mixture was stirred and a mixture of 115 μL of 40% Triton B in methanol and 38 μL of DBU was added. After a very mild exotherm, all solids dissolved. After 50 minutes at ambient temperature, the reaction was quenched by the addition of 0.5 mL of 3 N HCL. The mixture was filtered to remove floc, diluted with 2 volumes of water and extracted with butyl chloride. The extracts were water washed and stripped to an oil. This was chromatographed on 35 g of silica gel eluting with 5%→60% EtOAc in hexane to recover 2.2 g (65% yield.) of the desired product, Rf 0.18 (silica gel, EtOAc:hexane=1:4).