Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([OH:25])=O)=[CH:22][C:17]=2[C:16](=[O:26])[N:15]([C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH3:28])[C@@H:14]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:13]1=[O:43])=[O:7])(C)(C)C.F[P-](F)(F)(F)(F)F.[N:51]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].[Na].[OH-].[Na+]>CN(C=O)C.ClCCl.C(O)(C(F)(F)F)=O.CCO>[NH2:51][C:23]([C:21]1[CH:20]=[CH:19][C:18]2[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:6]([OH:5])=[O:7])[C:13](=[O:43])[C@H:14]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[N:15]([C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH3:28])[C:16](=[O:26])[C:17]=2[CH:22]=1)=[O:25]
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(C(=O)O)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)[C@@H]1c1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(C(N)=O)ccc2N(CCCCC(=O)O)C(=O)[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 65.1 %

Procedure:
A solution of (3S)-1-(4-tert-Butoxycarbonyl-butyl)-3-(4-chloro-phenyl)-4-[(R)-1-(4-chloro-phenyl)-ethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-7-carboxylic acid (Example 33) (63 mg, 0.10 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (57 mg, 0.15 mmol), HOBT (20 mg, 0.15 mmol) N,N-diisopropylethylamine (70 μL, 0.4 mmol), ammonium chloride (11 mg, 0.2 mmol) in DMF (400 μL) was stirred at room temperature for 1 h. under argon atmosphere. After evaporation of the solvent, the residue was diluted with EtOAc (15 mL), washed with water (10 mL), dried (Na2SO4) then concentrated to dryness under reduced pressure. Chromatography on silica (EtOAc/hexanes, 1:1) afforded anoil (58 mg), which was dissolved in dichloromethane (1.5 mL) and TFA (0.5 mL). This solution was stirred at room temperature for 10 h, then evaporated to dryness. The residue was dissolved in ice-cold water (10 mL) and AcONa (100 mg)/AcOH (100 μL) were added. The solution was extracted with ether (3×20 mL), then the organic layer was dried (Na2SO4) and concentrated to dryness under reduced pressure. Purification by column chromatography (EtOAc/CH2Cl2/EtOH, 5:4:1) afforded a colorless oil, which was converted to its sodium salt with NaOH 1N in EtOH. Recrystallization from EtOH/ether yielded title compound (37 mg, 62%) as a white powder: Mass spectrum (LCMS, ESI pos.): Calcd for C29H27Cl2IN3O5: 567.13; found 568.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:12]1([C:10](=[O:11])[CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]3)=[CH:3][CH:4]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CCc1ccc(Br)cc1)N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CCC(=O)N3CCOCC3)cc2)CC1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of Example 4B (400 mg, 1.342 mmol) in toluene (3.4 mL) at room temperature was treated with 1-tert-butoxycarbonylpiperazine (300 mg, 1.611 mmol), Pd2(dba)3 (61 mg, 0.0671 mmol), bis-tert-butyl biphenylphosphine (40 mg, 0.134 mmol) and sodium tert-butoxide (199 mg, 2.013 mmol), degassed three times by freeze-thaw cycle, stirred overnight and partitioned between ethyl acetate and saturated NH4Cl. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane to provide the desired product (317 mg, 59%). 1H NMR (300 MHz, CD3OD) δ 7.12 (2H, m), 6.91 (2H, br), 3.63 (8H, br), 3.53 (2H, t), 3.36 (2H, t), 3.10 (4H, br), 2.91 (2H, t), 2.58 (1H, t), 1.48 (9H, s).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[C:14]([CH2:15][OH:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:3][C@H:4]([C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:14]([CH2:15][OH:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[N:28]=[CH:27][N:26]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c(CO)c2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(CO)c2n1-c1ccccc1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
To a solution of [2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-yl]methanol dihydrochloride (159 mg, 0.45 mmol) in IPA (5 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (69 mg, 0.45 mmol) and DIPEA (228 μL, 1.33 mmol) and the reaction mixture heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 353 as a white solid (87 mg, 49%). 1H NMR 400 MHz δ (d6-DMSO): 7.78 (1H, s), 7.65-7.56 (2H, m), 7.55-7.38 (5H, m), 7.16 (2H, br s), 7.05 (1H, dd, J=10.6, 8.8 Hz), 5.15 (1H, quin, J=6.9 Hz), 4.51 (1H, t, J=5.0 Hz), 3.97 (2H, d, J=5.0 Hz), 1.43 (3H, d, J=6.9 Hz)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH:17]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:19]1[CH2:18][CH:17]([O:16][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([NH:8][C@H:9]3[CH2:14][CH2:13][C@@H:12]([CH3:15])[CH2:11][CH2:10]3)[N:4]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@@H](Nc2ncc(Br)c(OC3CNC3)n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-(5-bromo-2-(cis-4-methylcyclohexylamino)pyrimidin-4-yloxy)azetidine-1-carboxylate (6.5 g, 14 mmol) in DCM (25 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 4 h, diluted with DCM, washed with 1N NaOH solution, water, dried over sodium sulfate, filtered and concentrated to dryness. MS (ESI) m/z Calc. 340.1 (M+). Found: 342.1 (M++2).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:10][C:11](=[O:13])[CH3:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4]1.[CH3:14]I.O>CN(C=O)C>[CH3:14][N:10]([CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4]1)[C:11](=[O:13])[CH3:12]
Reactant: CI
Reactant: CC(=O)NC1C=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)C1C=CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
To a suspension (10 ml) of sodium hydride (0.24 g, 10 mmoles) in DMF was added N-(2-cycloheptenyl)acetamide (1.53 g, 10 mmoles) in DMF (1 ml) at 0° C. After completion of the addition, the temperature of the mixture was raised to room temperature, and after stirring for 15 minutes, methyl iodide (2.84 g, 20 mmoles) was added dropwise. The resulting mixture was stirred at room temperature for 24 hours, poured into water (20 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.84 g of N-methyl-N-(2-cycloheptenyl)acetamide [Compound (55)].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:21])[N:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>O1CCOCC1>[Br:21][C:4]1[N:3]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(Br)c1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.2 %

Procedure:
0.222 g (0.0005 mol) of 2,6-dibromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridine was dissolved in 10 ml of dioxan and treated with 0.047 g (0.00055 mol) of piperazine and 0.7 ml of triethylamine. The mixture was stirred at room temperature for 20 hrs. and subsequently at 40° C. for 3 hrs., the solvent was then removed and the residue was chromatographed on silica gel with 5% methanol in dichloromethane. There was obtained 0.14 g (62%) of 1-[6-bromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridin-2-yl]-piperazine as yellow crystals; m.p.: 160-162° C.
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[CH2:16][O:17][CH3:18])[C:7]=1[C:8]#[N:9])(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+]>CCO>[CH3:18][O:17][CH2:16]/[CH:15]=[CH:14]/[C:10]1[C:7]2[C:8]([NH2:9])=[N:2][S:1](=[O:4])(=[O:3])[NH:5][C:6]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COC/C=C/c1cccc(NS(N)(=O)=O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC/C=C/c1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
A solution of (E)-2-sulfamoylamino-6-(3-methoxyprop-1-enyl)benzonitrile (Example 97a) (139 mg, 0.5 mmol) in EtOH was treated with NaOH (2.0 N, 0.5 mL, 1.0 mmol), and the resultant solution was heated to 100° C., and stirred at that temperature for 4 h. After it was cooled down to room temperature, the clear reaction solution was filtered, and the filtrate was carefully neutralized with 10% AcOH while it was vigorously stirred at 0° C. The resultant precipitate was collected by filtration, washed with warm water, and 20% EtOH in water to give the title product (E)-5-(3-Methoxyprop-1-enyl)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (108 mg, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (s, 3H), 4.06 (dd, J=4.8, 1.2 Hz, 2H), 6.26 (dt, J=16.2, 5.0 Hz, 1H), 6.91-6.95 (m, 2H), 6.97 (bs, 1H), 7.16 (d, J=7.2 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 8.31 (s, 1H), 10.93 (s, 1H). 13C NMR (DMSO-d6) δ 58.4, 72.5, 111.6, 117.0, 122.4, 129.0, 132.5, 134.0, 138.1, 143.7, 162.9. MS 268 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]1[O:16][C@H:14]1[CH3:15].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+].[Cl-].[Na+]>C(OCC)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:13][C@@H:14]([OH:16])[CH3:15]
Reactant: Brc1ccccn1
Reactant: C[C@H]1CO1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOCC
Product: C[C@H](O)Cc1ccccn1
Reaction time: 0.08 h

Procedure:
2-Bromopyridine (1.58 g) was dissolved in diethyl ether (20 ml). To the solution was added at −60° C. n-butyllithium (1.6M hexane solution, 6.25 ml). The mixture was stirred for 5 minutes at the same temperature. To the reaction mixture were added (S)-(−)-propylene oxide (1.00 ml) and boron trifluoride diethyl etherate (1.23 ml) successively. The mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 5% sodium hydrogencarbonate (30 ml), which was then subjected to salting out with sodium chloride, followed by extraction with ethyl acetate (20 ml) five times. The organic layer was dried over anhydrous magnesium sulfate, which was then concentrated. The concentrate was purified by means of a column chromatography (carrier: silica gel: 50 g, eluted with ethyl acetate) to give the title compound (0.33 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1N1CCCCC1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 5 ml of piperidine gives 700 mg of the desired product: M+ =491.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(OC([NH:20][NH2:21])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH:20]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[NH2:21]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CNN)c1

Procedure:
A solution of 3 g of methyl 3-bromomethylbenzoate (13 mmol), 2.6 g of tert-butoxycarbonylhydrazine (19 mmol) and 3.1 g of potassium carbonate (23 mmol) in 30 ml of DMF is stirred at RT for 24 h. After water has been added, the reaction mixture is extracted with dichloromethane. The organic phase is dried, filtered and evaporated, and the residue is purified chromatographically. The BOC protecting group is then eliminated using 30 ml of hydrochloric acid (4 M in dioxane). Yield: 1.25 g
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)C4CC4)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[F:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C:40](O)=[O:41])=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:40]([C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30]([F:29])=[CH:31][CH:32]=1)=[O:41])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.03 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (196 mg, 1.03 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (297 mg, 1.55 mmol) and 1-hydroxy-1H-benzotriazole (158 mg, 1.03 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (520 mg, 90%).
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:10]=[C:9]([C:17]([O:19]CC)=[O:18])[C:8]2=[O:22])#[N:2].C(OC([NH:31][C:32]1([C@@H:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:34][CH2:33]1)=O)(C)(C)C.N12CCN(CC1)CC2>CS(C)=O>[NH2:31][C:32]1([C@@H:35]2[CH2:39][CH2:38][N:37]([C:4]3[C:3]([C:1]#[N:2])=[C:12]4[C:7]([C:8](=[O:22])[C:9]([C:17]([OH:19])=[O:18])=[CH:10][N:11]4[C@@H:13]4[CH2:15][C@@H:14]4[F:16])=[CH:6][CH:5]=3)[CH2:36]2)[CH2:34][CH2:33]1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C#N)c(F)ccc2c1=O
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: N#Cc1c(N2CC[C@@H](C3(N)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
A mixture of ethyl 8-cyano-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate (250 mg, 0.785 mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (267 mg, 1.18 mmol), 1,4-diazabicyclo[2.2.2]octane (132 mg, 1.18 mmol), and dimethyl sulfoxide (13 ml) was stirred for 2 hours at room temperature under a nitrogen-replaced atmosphere. After evaporating the solvent, the residue was partitioned in chloroform (30 ml) and 10% aqueous citric acid solution (30 ml), and the organic layer was separated. The organic layer obtained was dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The residue was dissolved in concentrated hydrochloric acid (4 ml) and glacial acetic acid (4 ml) at room temperature and then stirred for 12 hours while heating in an oil bath at 110° C. After evaporating the solvent, concentrated hydrochloric acid (2 ml) and water (20 ml) were added, and the solution was transferred into a separation funnel and then washed with chloroform (50 ml). 10 mol/l Aqueous sodium hydroxide solution was then added to the aqueous layer after washing, thereby adjusting the pH to >12. Then after washing with chloroform (50 ml), the pH was adjusted to 8.3 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid. The aqueous layer obtained was then concentrated to 5 ml under a reduced pressure, subject to extraction into chloroform:methanol=10:1 (50 ml×3), and the combined organic layer was dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The yellow solids thus obtained were recrystallized in ethanol and then dried under a reduced pressure to obtain 124 mg (40%) of the title compound as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[O:15][C:14]([CH3:24])([CH3:23])[C:13]32[CH2:26][CH2:25]3)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:36]([C:33]4[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=4)=[O:37])[CH:20]=3)[O:15][C:14]([CH3:24])([CH3:23])[C:13]32[CH2:25][CH2:26]3)[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21CC1
Reactant: COc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(NC(=O)OC(C)(C)C)=N2)C2(CC2)C(C)(C)O3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a mixture of tert-butyl[(4′R)-6′-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (100 mg, 0.268 mmol), 5-methoxypyrazine-2-carboxylic acid (45 mg, 0.30 mmol) and 1H-benzotriazol-1-ol (40 mg, 0.29 mmol) in dichloromethane (2 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol). The mixture was stirred at room temperature for 3 hours and directly purified by silica gel column chromatography (precolumn: NH-silica gel, main column: neutral silica gel, hexane/ethyl acetate=2:1-1:1-0:1) to afford tert-butyl[(4′R)-6′-{[(5-methoxypyrazin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (108 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.CC([O-])=O.[Na+].Br[CH2:16][C:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]2[CH:16]=[C:17]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:9][C:4]=2[N:3]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2cc3c(O)nc(N)nc3[nH]2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2,6-diaminopyrimidin-4-ol (1 g, 7.93 mmol) and NaOAc (0.846 g, 10.31 mmol) in water (180 mL) was heated to 100° C. for 20 minutes. To this was added a suspension of 4-(2-bromoacetyl)benzonitrile (2.2 gm, 8.73 mmol) [prepared according to procedure mentioned in J. Med. Chem., 2011, 54(12), 4042-4056] in MeOH (25 mL) and heated overnight at 100° C. After completion of reaction, the reaction mixture was cooled to 0° C. Resultant solid product was filtered off and dried under reduced pressure to provide title compound XI-10-I (1.2 g, 100%). LCMS: m/z 252 (M+1)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[F:10][C:11]([F:25])([F:24])[C:12]([NH:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:13]>ClCCCl>[Cl:5][CH2:6][C:7]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][C@H:15]2[NH:14][C:12](=[O:13])[C:11]([F:24])([F:10])[F:25])=[CH:19][CH:20]=1)=[O:8]
Reactant: O=C(N[C@@H]1CCc2ccccc21)C(F)(F)F
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)c1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)CC2
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To a suspension of AlCl3 (89.2 g, 0.67 mol) in 1,2-dichloroethane (600 ml) was added chloroacetyl chloride (55.7 ml, 78.9 g, 0.7 mol) dropwise at 0-5° C. under nitrogen for 20 minutes and it was then left to warm up to 20-25° C. To this mixture was added N-trifluoroacetyl-(R)-1-aminoindan (34.4 g, 0.15 mol) for 3 hours at 20-25° C. The resulting mixture was then stirred for an additional 30 minutes and poured into a mixture of ice-cold water (1.5 l) and 1,2-dichloroethane (1l). The mixture was stirred for 5 minutes and the layers were separated. The aqueous layer was extracted with 1,2-dichloroethane (2×750 ml). The combined organic layers were washed with water (2×900 ml) and 5% aqueous NaHCO3 solution (3×900 ml). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give a solid, which was recrystallized from ethanol to give 15 g (48%) of a white solid mp: 166-167° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCCC=CCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: NCCCCC=CCCCCN
Temperature: 25 °C

Procedure:
The 1,10-dipthalimido-dec-5-ene (1 equiv.) and hydrazine (2 equiv.) are stirred in ethanol at reflux. The reaction mixture is cooled to room temperature and the resulting solid is filtered off. The filtrate is purified via silica gel chromatography to yield 1,10 diamino-dec-5-ene.