Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:34][C:35]1[CH:59]=[CH:58][C:38]([O:39][C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]3[N:47](C(OC(C)(C)C)=O)[CH:48]=[CH:49][CH:50]=3)[CH:41]=2)=[CH:37][CH:36]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.C(Cl)Cl.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([O:39][C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]3[NH:47][CH:48]=[CH:49][CH:50]=3)[CH:41]=2)=[CH:58][CH:59]=1)=[O:9]
Reactant: Cc1ccoc1C(=O)O
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cc(Oc2ccc(N)cc2)ccn1
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
Solvent: O
Product: Cc1ccoc1C(=O)Nc1ccc(Oc2ccnc(-c3ccc[nH]3)c2)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A mixture of 3-methyl-2-furoic acid (70 mg, 0.55 mmol), HATU (243 mg, 0.64 mmol), tert-butyl 2-[4-(4-aminophenoxyl)pyridin-2-yl]-1H-pyrrole-1-carboxylate (160 mg, 0.46 mmol) and N,N-diisopropylethylamine (148 mg, 1.15 mmol) in anhydrous DMF (10 ml) was stirred at 45° C. for 2 hours. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was dissolved in 5 ml of methylene chloride, followed by addition of trifluoroacetic acid (3 ml). The mixture was stirred at room temperature for 16 hours. The solvents were evaporated under reduced pressure. The residue was purified by reversed-phase chromatography with a gradient of 10˜50% acetonitrile/water to give 3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide as white solid. Yield: 56 mg, 34%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Br[CH2:27][C:28]([OH:30])=[O:29]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)[CH:5]=[C:6]([CH3:9])[C:7]=1[O:8][CH2:27][C:28]([OH:30])=[O:29]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (350 mg, 0.988 mmol, Intermediate 10) in isopropanol (5 mL) and 3 N aq. NaOH (1.5 mL) is treated with bromoacetic acid (274 mg, 1.98 mmol). The dark red reaction mixture is stirred at 70° C. After 1, 2, 3 and 18 h an additional portion of bromoacetic acid (274 mg, 1.98 mmol) and 3N aq. NaOH (1.5 mL) is added and stirring is continued for 2 h after the last addition. The reaction mixture is diluted with EA, and washed with 1 N aq. HCl. The aq. phase is extracted with EA. The combined organic extracts are dried over MgSO4 and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 10% of methanol to give {2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-acetic acid (60 mg) as a pale yellow oil; LC-MS: tR=1.07 min, [M+1]+=413.23.
Reaction SMILES: C(C(NC(C1C=CC=CC=1S[S:19][C:20]1[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=1[C:22]([NH:24][CH:25]([CH:29]([CH3:31])[CH3:30])[C:26]([OH:28])=[O:27])=[O:23])=O)CC(C)C)(O)=O.BrBr>>[CH3:30][CH:29]([CH3:31])[CH:25]([N:24]1[C:22](=[O:23])[C:21]2[CH:32]=[CH:33][CH:34]=[CH:35][C:20]=2[S:19]1)[C:26]([OH:28])=[O:27]
Reactant: CC(C)CC(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(C(=O)O)C(C)C)C(=O)O
Agent: BrBr
Product: CC(C)C(C(=O)O)n1sc2ccccc2c1=O
Yield: 0.1 %

Procedure:
Following the procedure of Example 13, 6.0 g (13.6 mol) of 2-[2-[2-(1-carboxy-3-methylbutyl carbamoyl)phenyldisulfanyl]benzoylamino]-3-methylbutanoic acid was reacted with bromine to provide 2.25 g of the title compound, mp 166-168° C.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][NH:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]([CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:2]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: CCN(CC)CCNCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
tert-Butyl 4-chlorocarbonyl-piperazine-1-carboxylate (245 mg, 0.99 mmol) was added to a solution of N1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamine (235 mg, 0.98 mmol) and N,N-diisopropylethylamine (0.54 mL, 2.94 mmol) in DCM (2 mL). The reaction mixture was allowed to stir at room temperature for 1 hour. The mixture was quenched with saturated NH4Cl (2 mL) and extracted with DCM (2×5 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 4-(N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (200 mg, 45%). 1H NMR (CDCl3, 400 MHz) 7.32 (d, J=8.4 Hz, 2 H), 7.19 (d, J=8.4 Hz, 2 H), 4.42 (s, 2 H), 3.45-3.40 (m, 4 H), 3.25-3.20 (m, 4 H), 3.18 (t, J=6.8 Hz, 2 Hz), 2.56 (t, J=6.8 Hz, 2 H), 2.49 (q, J=7.2 Hz, 4 H), 1.46 (s, 9 H), 0.99 (t, J=7.2 Hz, 6 H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:18]1([N:23]2[C:32]3[N:31]=[C:30]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:43](O)=[O:44])=[C:38]5[C:42]=4[O:41][CH2:40][CH2:39]5)[N:29]=[CH:28][C:27]=3[N:26]([CH3:46])[C:25](=[O:47])[C@H:24]2[CH2:48][CH3:49])[CH2:22][CH2:21][CH2:20][CH2:19]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl.O>[CH:18]1([N:23]2[C:32]3[N:31]=[C:30]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:43]([NH:17][C@H:14]5[CH2:15][CH2:16][C@@H:11]([N:8]6[CH2:9][CH2:10][N:5]([CH2:4][CH:1]7[CH2:2][CH2:3]7)[CH2:6][CH2:7]6)[CH2:12][CH2:13]5)=[O:44])=[C:38]5[C:42]=4[O:41][CH2:40][CH2:39]5)[N:29]=[CH:28][C:27]=3[N:26]([CH3:46])[C:25](=[O:47])[C@H:24]2[CH2:48][CH3:49])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (139 mg, 0.40 mmol), 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (175 mg, 0.40 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (128 mg, 0.40 mmol) and diisopropylethylamine (258 mg, 2.08 mmol) were dissolved in 50 mL of dichloromethane. The reaction solution was stirred for 2 hours followed by the addition of 50 mL of water and 10 mL of aqueous ammonia successively, and stirred for another 0.5 hours. The resulting solution was extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-2,3-dihydrobenzofuran-4-carboxamide 12 (160 mg, yield: 61.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([NH2:17])=S)=[CH:4][CH:3]=1.[OH-].[K+].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]#[N:17])=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccccc1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1ccccc1-c1ccc(Cl)cc1

Procedure:
A suspension of N-(4'-chloro-2-biphenylyl)thiourea (7.1 g) in water (60 ml) was reacted with potassium hydroxide (15.1 g) in water (60 ml). Lead acetate trihydrate (10.3 g) in water (60 ml) was added and the mixture heated at 90°-95° C. for 1 hour to give 4'-chloro-2-biphenylylcyanamide (m.p. 106°-107° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4C(OC(C)(C)C)=O)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][C@@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:16])([CH3:17])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2sc(-c3nc(NCCN4C(=O)NC(=O)C4(C)C)ncc3Br)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc(OC[C@@H]4CCCN4)ccc3s2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (2S)-tert-butyl 2-((2-(5-bromo-2-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino)pyrimidin-4-yl)benzo[b]thiophen-5-yloxy)methyl)pyrrolidine-1-carboxylate (146 mg, 0.222 mmol) in dichloromethane (5 mL) was treated with trifloroacetic acid (1 mL) and stirred at room temperature for 30 min. The reaction was concentrated in vacuo to yield the title compound as a bright yellow solid (213 mg, quantitative yield). MS (M+H)+ 559/561.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)=[O:4].[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Nc1ccc(NC(=O)CCl)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-methanesulfonylamino-phenyl)-acetamide and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 102-106° C. (hexane)
Reaction SMILES: C([O-])(=O)C.[K+].N[C@@H]1C2C(=CC=CC=2)C[C@H]1NC(C1NC2C(C=1)=CC(Cl)=CC=2)=O.C(O)(C(F)(F)F)=O.[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][C@@H:49]1[CH2:57][C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]1[NH:58][CH2:59][C@@H:60]1[CH2:64][O:63]C(C)(C)[O:61]1)=[O:47])=[CH:40]2>CO.C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][C@@H:49]1[CH2:57][C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]1[NH:58][CH2:59][C@@H:60]([OH:61])[CH2:64][OH:63])=[O:47])=[CH:40]2
Reactant: CC1(C)OC[C@@H](CN[C@@H]2c3ccccc3C[C@H]2NC(=O)c2cc3cc(Cl)ccc3[nH]2)O1
Agent: CC(=O)[O-]
Agent: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1Cc2ccccc2[C@H]1NC[C@@H](O)CO)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
2,3-O-(S)-Isopropylidene-L-glyceraldehyde (98 mg, 0.75 mmol) and potassium acetate (75 mg, 0.75 mmol) were added to a solution of N-{(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl}-5-chloro-1H-indole-2-carboxamide (Method 5, 328 mg, 0.75 mmol) in MeOH (10 mL). The reaction was stirred at ambient temperature for approximately 5 mins then macroporous triethylammonium methyl polystyrene cyanoborohydride (352 mg, 0.9 mmol) was added and the reaction stirred at ambient temperature for a further 5 h. The reaction was then filtered and the volatiles were removed by evaporation under reduced pressure to 5-chloro-N-[(1R,2R)-1-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)-2,3-dihydro-1H-inden-2-yl]-1H-indole-2-carboxamide which was used crude in the next stage. TFA (3 mL) was added to a solution of 5-chloro-N-[(1R,2R)-1-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)-2,3-dihydro-1H-inden-2-yl]-1H-indole-2-carboxamide (100 mg, 0.23 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 24 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (90 mg, 100%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:17]=[N:18][N:19](C5CCCCO5)[CH:20]=4)=[CH:14][N:13]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.O1CCOCC1>[N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:20]=[N:19][NH:18][CH:17]=4)=[CH:14][N:13]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnn(C3CCCCO3)c2)c2c(N3CCOCC3)ncnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(-c2cn[nH]c2)c2c(N3CCOCC3)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(morpholin-4-yl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C19) (4.0 g, 8.2 mmol) in dichloromethane (20 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 100 mL). The reaction mixture was stirred at room temperature for 2 hours, then poured into a mixture of ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 10% to 80% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 2.18 g, 5.44 mmol, 66%. LCMS m/z 401.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.78 (s, 2H), 7.19 (s, 1H), 5.64 (s, 2H), 3.56-3.66 (m, 6H), 3.34-3.40 (m, 4H), 0.91-0.98 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16]#[N:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:25][OH:26]>C(O)C>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[N:25][OH:26])[NH2:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)c1cc(C#N)cc2c1OCC2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(C(N)=NO)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A mixture of 7-tert-butyl-5-cyano-2,3-dihydro-3,3-dimethylbenzo[b]furan (6.39 g, 27.9 mmol), potassium carbonate (15.80 g, 114.0 mmol), hydroxylamine hydrochloride (7.93 g, 114.0 mmol), and 135 mL of ethanol is heated at reflux for 20 h. The reaction mixture is cooled to room temperature, filtered, and concentrated in vacuo to give a solid residue. Purification by flash column chromatography on silica gel (20% ethyl acetate-hexane→5% methanol-dichloromethane) furnishes about 3.13 g (43%) of the title compound as a colorless foamy solid: mp 109°-110 ° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].Br[CH2:18][CH:19]=[CH2:20].[In]>CO.O>[CH2:20]([C:2]1([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH:19]=[CH2:18]
Reactant: O=C1CCCC1C(=O)OCc1ccccc1
Reactant: C=CCBr
Agent: [In]
Solvent: CO
Solvent: O
Product: C=CCC1(O)CCCC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl 2-oxocyclopentanecarboxylate (from step A, 5 g, 22.91 mmol) in a mixture of methanol (20 ml) and water (60.00 ml) was added 3-bromoprop-1-ene (8.31 g, 68.7 mmol) and indium (1.081 ml, 68.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and to the residue was added 1N hydrogen chloride (15 mL) and stirred at room temperature for 5 min. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (4 mL). The ethyl acetate layer is washed with brine (4 mL), dried over anhydrous Na2SO4 and concentrated under the reduced pressure. The residue was subjected to preparative HPLC (Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM). The desired fractions were collected, concentrated under reduced pressure to yield the desired product as a diastereomer mixture. The diastereomer mixture was subjected to chiral preparative HPLC to yield four individual isomers. The fractions corresponding to the second isomer was concentrated and freeze dried to yield a solid (800 mg, 3.08 mmol, 13.4% yield). Chiral HPLC method: Column. ChiralPak AD-H, 250×3 cm, 5 μm; Flow rate: 130 mL/min; Mobile Phase: CO2/MeOH=70/30; Inj. Vol.=0.7 mL, Wavelength=220 nM,: Retention time=3.18 min. MS (ESI+)=283 (M+Na)+
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31](O)=[C:30]([F:36])[CH:29]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[Br:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31]([O:1][C@H:2]2[CH2:6][CH2:5][O:4][C:3]2=[O:7])=[C:30]([F:36])[CH:29]=1
Reactant: O=C1OCC[C@H]1O
Reactant: Cc1cc(O)c(F)cc1Br
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(O[C@H]2CCOC2=O)c(F)cc1Br
Temperature: 0 °C
Yield: 50 %

Procedure:
(R)-3-hydroxydihydrofuran-2(3H)-one (2.0 g, 20 mmol) was suspended in Toluene (150 mL) and triphenylphosphine (6.2 g, 24 mmol) and 4-bromo-2-fluoro-5-methylphenol (4.8 g, 24 mmol) were added and cooled to 0° C. The solution was degassed with nitrogen bubble for 10 minutes. Di-tert-butyl diazene-1,2-dicarboxylate (5.4 g, 24 mmol) was dissolved in toluene (40 mL) and added to the reaction over 5 minutes. The reaction was allowed to slowly warm to ambient temperature overnight. The toluene was removed and the oily residue was purified over silica gel (20 to 40% EtOAc in hexanes) to afford (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)dihydrofuran-2(3H)-one (2.9 g, 10 mmol, 51% yield).
Reaction SMILES: [BrH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH2:9]O)[CH:8]=1>C(Cl)(Cl)Cl>[Br:1][CH2:9][C:7]1[CH:8]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: Br
Reactant: COc1ccc(F)cc1CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(F)cc1CBr
Reaction time: 1 h

Procedure:
Add Sodium borohydride (540 mg, 13.95 mmol) in portions to a solution of 5-Fluoro-2-methoxy-benzaldehyde (2.15 g, 13.94 mmol) in absolute EtOH (20 ml) and stir at room temperature. After 1 h, evaporate the solvent, dilute the residue in CH2Cl2 and treat with aqueous 3M HCl. Separate the phases, wash the organic one twice with H2O, dry over Na2SO4 and concentrate at vacuum to obtain pure (5-Fluoro-2-methoxy-phenyl)-methanol as white solid. Add aqueous concentrated HBr (15 ml) to a solution of (5-Fluoro-2-methoxy-phenyl)-methanol (1.9 g, 12.17 mmol) in CHCl3 (10 ml) and stir at room temperature. After 1 h, separate the phases, wash the aqueous one with CH2Cl2, combine organic phases, wash with H2O, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford 2-Bromomethyl-4-fluoro-1-methoxy-benzene as white solid. 1H-NMR (CDCl3, 200 Mz): δ 7.06 (dd, J=3.0 and 8.6 Hz, 1H), 6.98 (m, 1H), 6.81 (dd, J=4.4 and 9.0 Hz, 1H), 4.50 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH:9]([CH3:13])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:22])[CH:9]([CH3:13])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Solvent: c1ccncc1
Product: CC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S
Yield: 28.5 %

Procedure:
A stirred mixture of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4 -benzodiazepin-2-one (10 g, 0.035 mol) in pyridine (300 ml), treated with P2S5 (8.0 g, 0.036 mol) was refluxed, under N2, for 2 hours then concentrated in vacuo. To remove the remaining pyridine the residue was combined with toluene twice with concentration after each addition. The remaining material was mixed with cold NaHCO3 and extracted twice with CH2Cl2. At this point a precipitate thought to be undissolved product formed between the two layers. This was filtered and washed with CH2Cl2 and H2O . The NaHCO3 layer was extracted with CH2Cl2 again. The combined CH2Cl2 extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was crystallized from EtOAc-Skelly B to give 3.0 g of the subtitled intermediate, mp 250°. The precipitate was also recrystallized from EtOAc-Skelly B to give 3.01 g of additional subtitled intermediate, mp 255°.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].CCN(CC)CC.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:15][O:14][C:12]([C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:8]=[C:9]([CH3:11])[CH:10]=2)[C:2]=1[NH:1][C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13]
Reactant: COC(=O)c1cnc2cc(C)nn2c1N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cnc2cc(C)nn2c1NC(=O)Cc1ccccc1
Temperature: 80 °C

Procedure:
A 250 mL round-bottomed flask containing methyl 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (1.10 g, 5.0 mmol, 1 eq.), CH2Cl2 (40 mL), and Et3N (2.04 g, 20 mmol, 4 eq.) was added slowly phenylacetyl chloride (6.16 g, 40 mmol, 8 eq.). Then the mixture was heated at 80° C. for 4 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (40 mL) and water (25 mL). The aqueous phase was extracted with CH2Cl2 (2×15 mL). The combined organic solution was dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography using MeOH and CH2Cl2 as the mobile phases to furnish Compound (20-1) as a yellowish solid.