Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[N:27]([CH3:29])[CH3:28]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[N:27]([CH3:29])[CH3:28]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: CN(C)c1ccc(B(O)O)cc1Cl
Product: CN(C)c1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 96.9 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.25 g (6.48 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.68 g (8.42 mmol) of 3-chloro-4-(N,N-dimethylamino)phenylboronic acid (Step 2). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 2.65 g (97%) of 2-chloro-4-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-N,N-dimethylbenzenamine as a colorless solid: mp 129.0°-130.0° C.; NMR (CDCl3) β 2.81 (s, 6H), 3.05 (s, 3H), 6.76-6.91 (m, 2H), 7.08(d, J=2 Hz, 1H), 7.17-7.26 (m, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.83(d, J=8.5 Hz, 2H). MS (FAB): m/e 428 (M+Li). Anal. Calc'd for C21H18 ClF2NO2S: C, 59.79; H, 4.30; N, 3.32. Found: C, 59.40; H, 4.29; N, 3.24.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:22]=[C:11]2[C:12]([C@@H:16]3[CH2:18][C@H:17]3[CH:19]=[N:20]O)=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]1[CH:22]=[C:11]2[C:12]([C@@H:16]3[CH2:18][C@H:17]3[CH2:19][NH2:20])=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1
Reactant: Cc1cc2c([C@@H]3C[C@H]3C=NO)cccn2n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a suspension of lithium aluminum hydride (1.18 g, 31.0 mmol) in tetrahydrofuran (70 mL) was added a solution of trans-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropanecarbaldehyde oxime (1.67 g, 7.76 mmol) in tetrahydrofuran (8 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. Sodium sulfate decahydrate (17 g) was added under ice-cooling, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound (1.39 g, yield 89%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:12])OCC)[CH:3]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)=[NH:12]
Reactant: CCOC(=N)c1cccnc1
Reactant: COC(CN)OC
Agent: Cl
Product: COC(CNC(=N)c1cccnc1)OC

Procedure:
Ethyl 3-pyridinecarboximidate hydrochloride and aminoacetaldehyde dimethyl acetal were subjected to a procedure similar to that described in Example 8.b. to provide pure N-(2,2-dimethoxyethyl)-3-pyridinecarboxamidine as an oil; MS: m/z=210(M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]1([CH2:22][O:21][C:19](=[O:20])[CH2:18][NH:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:16][CH:15]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
4-Benzyloxyaniline hydrochloride (5.893 g, 25 mmol) was added to a solution of benzyl bromoacetate (4.0 ml, 25 mmol) in 25 ml of dry dimethylformamide. Sodium acetate (2.051 g, 25 mmole) and 13.82 g (0.1 mole) of potassium carbonate were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted from water with three portions of ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The volatiles were removed, and the residue was purified by flash column chromatography on silica (LPS-1) (eluting with 15% ethyl acetate/hexane) to yield 5.64 g of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([C:21]=2[CH:30]=[O:31])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(COc2ccc(Cl)cc2)c(C=O)c2ccccc21
Temperature: 55 °C

Procedure:
Under a nitrogen atmosphere a round bottom flask was charged with 0.63 ml of anhydrous N,N-dimethylformamide. The reaction vessel was placed in a −20° C. bath and then phosphorous oxychloride (0.187 ml, 0.310 g, 2.02 mmol) was carefully added. The resulting mixture was stirred in an ice bath for about twenty minutes and 2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indole (0.50 g, 1.84 mmol) in 3.4 ml of N,N-dimethylformamide, was added. The resulting mixture was stirred at room temperature for about ninety minutes. The reaction mixture was then placed over an oil bath and heated to 55° C. and maintained at this temperature for about one hour. The reaction mixture was then permitted to cool to room temperature and was then poured into water. Sodium hydroxide (10 ml of a 5.0 N solution) was added and heated to reflux. The resulting mixture was cooled and the solids were then collected by filtration.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:38])=[C:34](Cl)[N:35]=3)[C:30](=[O:39])[C:29]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C.N1C=CC=CC=1>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:38])=[C:34]([N:10]4[CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[CH:5][N:4]=[N:3]5)[CH2:8][CH2:9]4)[N:35]=3)[C:30](=[O:39])[C:29]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cn(C2CCNCC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCC(n4ccnn4)CC3)c(F)cc2c1=O
Temperature: 100 °C
Yield: 66 %

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (225 mg, 1.2 mmol) and DBU (182 mg, 1.2 mmol) was added to a suspension of ethyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (150 mg, 0.48 mmol) in a mixture of acetonitrile (10 ml) and pyridine (3 ml). The reaction mixture was heated at 100° C. for 5 hrs. The suspended solid was filtered and the filtrate was concentrated to dryness. The residue was triturated with water and separated solid was filtered, washed with water and dried to give 135 mg of desired product. m.p. 213°-214° C.; 1H NMR (CDCl3) δ: 8.48 (s, 1H), 8.11 (d, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 4.60-4.85 (m, 3H), 4.29-4.40 (q, 2H), 3.43-3.54 (m, 1H), 3.21-3.35 (m, 2H), 2.10-2.36 (m, 4H), 1.36 (t, 3H), 0.95-1.23 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=O)[NH:6][C:5]2=[O:15].[Sn]>CCO>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[NH2:1])[C:5](=[O:15])[NH:6][CH2:7]2
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: [Sn]
Solvent: CCO
Product: Nc1cc2c(cc1N)C(=O)NC2
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A solution of 5-Amino-6-nitroisoindoline-1,3-dione (1.0 g, 4.83 mmol) and tin powder (5.8 g, 48.3 mmol) in EtOH (30 mL) was heated at 90° C. for 4 h. The reaction mixture was cooled to RT, filtered the precipitated solid, washed with EtOH (10 mL) and dried to afford 5,6-diaminoisoindolin-1-one (0.75 g, 95%) as a yellow solid. LCMS: 164 (M+1). 1H NMR (300 MHz, DMSO-d6): δ 4.25 (s, 2H); 7.93 (s, 1H), 7.41 (s, 1H); 8.22 (s, 1H); 9.0 (br.s, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][Cl:19].[OH-].[Na+]>CN(C)C=O.O>[Cl:19][CH2:18][CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Dissolve 4-hydroxybenzaldehyde (0.082 mol) in dimethylformamide (100 ml) and add potassium carbonate (0.164 mol) and 1-bromo-2-chloroethane (0.246 mol). Stir magnetically for five days at ambient temperature, then hydrolyse the reaction mixture in 500 ml of water and render alkaline with 3 g of sodium hydroxide pellets. Extract twice with 50 ml of ether each time. Dry the organic phase over magnesium sulphate and remove the ether by evaporation under reduced pressure. Purify the resulting oil by flash chromatography using a 9/1 cyclohexane/ether mixture as eluant. Subsequently, remove the mixture of solvents by evaporation under reduced pressure and crystallise the resulting yellow oil and store it in a dessicator.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)([CH2:12][OH:13])[CH:9]([F:11])[F:10])(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[NH2:7][C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)([CH:9]([F:10])[F:11])[CH2:12][OH:13]
Reactant: CC(C)(C)OC(=O)NC(CO)(c1cccc(Br)c1)C(F)F
Agent: Cl
Solvent: C1COCCO1
Product: NC(CO)(c1cccc(Br)c1)C(F)F
Reaction time: 0.75 h

Procedure:
[1-(3-Bromo-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (8.408 g, 22.96 mmol) was dissolved in 105 ml 4 N HCl in dioxane. The reaction was stirred for 45 min. After completion volatiles were removed under reduced pressure to yield a white solid. 1H-NMR (360 MHz, DMSO-d6): 9.30 (br, 3H, NH3+), 7.85 (s, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 7.49 (t, 1H), 6.63 (t, 1H, CHF2), 6.03 (br, 1H), 4.05 (m, 2H); MS: 266 [(M+H)+].
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH:29][CH3:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:29]([CH3:30])[CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CNC
Solvent: CC#N
Product: CN(C)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-methylmethanamine (0.5 ml, 2.0 M in MeOH), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 305 (M+, 0.4), 85 (2), 84 (3), 63 (2), 59 (4), 58 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[CH2:37]([O:39][C:40](=[O:49])[CH2:41]C1C=NC=C(Cl)N=1)[CH3:38].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(#N)C>[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:15]1[CH:16]=[C:17]2[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)(=[O:29])=[O:28])[C:12]2=[N:13][CH:14]=1)[CH3:38]
Reactant: CCOC(=O)Cc1cncc(Cl)n1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Product: CCOC(=O)Cc1cnc2c(c1)c(-c1ccccc1OC)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Yield: 74.8 %

Procedure:
3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (938 mg, 3.02 mmol), (6-Chloro-pyrazin-2-yl)-acetic acid ethyl ester (605 mg, 3.02 mmol), palladium acetate (20.8 mg, 0.093 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (76.3 mg, 0.186 mmol) were combined under nitrogen. Acetonitrile (10 mL) and 1 M potassium carbonate (5.5 mL, 5.5 mmol) were added and the vial was flushed with nitrogen, capped and heated at 80° C. for 15 h. The layers were separated. The organics were diluted with ethyl acetate and washed with brine (1×), dried over sodium sulfate and adsorbed onto silica gel. The material was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford {6-[3-(2-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl-acetic acid ethyl ester (1.05 g, 64%). MS: m/z 453 (M+H+).
Reaction SMILES: [Mg].II.BrCCBr.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[CH:23]1[C:33]2[CH2:32][CH2:31][C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:28]2([OH:38])[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[CH2:31][CH2:32][C:33]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)=[CH:18][CH:17]=1
Reactant: Brc1ccc(COC2CCCCO2)cc1
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OC1(c2ccc(COC3CCCCO3)cc2)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
A mixture of magnesium turnings (1.07 g, 0.044 mol) activated with iodine, 1,2-dibromoethane and tetrahydrofuran (40 ml) was kept under a nitrogen atmosphere, and a solution of 4-bromophenylmethyl tetrahydro-2-pyranyl ether (11.20 g, 0.041 mol) in tetrahydrofuran (40 ml) was added dropwise under stirring. The mixture was gently heated to reflux temperature, and heating was continued for 3 h. The mixture was cooled to room temperature, and a solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (6.86 g, 0.033 mol) in tetrahydrofuran (40 ml) was added dropwise. The mixture was heated at reflux temperature for 1 h, cooled and then poured into an ice-cold saturated solution of ammonium chloride (85 ml). The mixture was extracted with ether (120 ml and 2×70 ml), and the combined organic layers were washed with water (2×40 ml), brine (40 ml) and dried (MgSO4). The solvent was removed in vacuo and the oily residue (14.7 g) was purified by column chromatography on silica gel (200 g) using first benzene and then a mixture of dichloromethane and ethanol (9:1) as eluents. The dichloromethane/ethanol fraction afforded 5.5 g (41%) of 5-(4-(2-tetrahydropyranyloxymethyl)phenyl)-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ol.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[S:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:24]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[S:21][C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:24]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1nc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)sc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cc2nc(CCC(=O)O)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-phenyl-4-thiazolyl]propionate (487 mg), lithium hydroxide hydrate (117 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1.5 hrs. 1N Hydrochloric acid (2.8 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-phenyl-4-thiazolyl]propionic acid (434 mg, yield 92%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 119–120° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:20][CH2:19]1)=[O:17])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:14][CH:9]2[CH2:10][O:11][CH2:12][CH2:13][NH:8]2)=[O:17])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCC1COCCN1)N1CCN(c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To 3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (170 mg, 0.39 mmol) in DCM (5 mL) at 0° C. was added TFA (1 mL in 5 mL DCM). The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo and the residue suspended between sat aq NaHCO3 (10 mL) and DCM (10 mL). The aqueous phase was extracted with DCM (2×10 mL). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give morpholin-3-ylmethyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (104 mg, 79%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:19]=[O:20])C>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[O:20])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2cc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Cl)ccc12
Temperature: 45 °C

Procedure:
A mixture of 6-chloro-1H-indole (2.0 g, 13.2 mmol) and POCl3 (1.34 mL, 14.5 mmol) in DMF (5 mL) is heated at 45° C. for 1 h. After completion, the reaction mixture is quenched with aqueous NaHCO3, Et2O is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless powder; ES-MS: M+=179.9; HPLC: AtRet=3.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][CH:6]([CH2:19][CH3:20])[C:7]([NH:9][C:10]([CH3:18])([CH3:17])[C:11]#[C:12][CH2:13][CH2:14][CH2:15]Cl)=[O:8].C(=O)([O-])[O-].[K+].[K+].[NH:31]1[CH:35]=[N:34][CH:33]=[N:32]1.CCCCCC.C(OCC)(=O)C>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][CH:6]([CH2:19][CH3:20])[C:7]([NH:9][C:10]([CH3:18])([CH3:17])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)=[O:8]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCn1cncn1
Temperature: 90 °C

Procedure:
To a stirred solution of 2-(3,5-dichlorophenoxy)-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide (0.59 g) in dry N,N-dimethylformamide (10 ml) containing anhydrous potassium carbonate (0.28 g) was added 1,2,4-triazole (0.10 g). The mixture was heated to 90° C. for 2.75 hours, cooled to ambient temperature, diluted with water and extracted with ethyl acetate (three times). The extracts were combined, washed with brine, dried over magnesium sulphate then evaporated under reduced pressure to give a yellow oil. The oil was fractionated by chromatography (silica; hexane/ethyl acetate, 2:1 by volume followed by ethyl acetate) to give the required product as a colourless oil, 0.16 g, 1H NMR (CDCl3) δ: 1.00-1.06(3H, t); 1.60(3H, s); 1.62(3H, s); 1.92-2.14(6H, m); 4.38-4.44(3H, m); 6.26(1H, s); 6.84(2H, s); 7.04(1H, s); 7.96(1H, s); 8.32(1H, s).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]4[CH2:34][CH2:33][CH2:32][CH2:31][C:25]=4[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11].C(OC(C1C=NN(C2NC(=O)C3C4CCCCC=4C=CC=3N=2)C=1)=O)C.Cl[CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66]>C1COCC1.CCOC(C)=O>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:29]([CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]4[CH2:34][CH2:33][CH2:32][CH2:31][C:25]=4[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Reactant: COCCOCCl
Agent: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)n2COCCOC)CCCC4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
DIEA (0.76 mL, 4.4 mmol) was added to a 2:1 mixture of 1-(4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester and 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.500 g, 1.478 mmol) in THF (7.4 mL), followed by 1-chloromethoxy-2-methoxy-ethane (0.186 mL, 1.63 mmol). The reaction mixture was stirred at room temperature for 18 h, diluted with EtOAc (40 mL), and washed with water (30 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers were washed with brine (40 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (5-60% EtOAc/hexanes) to yield the titled compound (0.257 g, 41% yield) and 1-[2-(2-methoxy-ethoxymethyl)-1-oxo-1,2,7,8,9,10-hexahydro-benzo[t]quinazolin-3-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (69.0 mg, 11% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].CN(C)C=O.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[CH:9]=[CH:10][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Temperature: 25 °C
Yield: 140.2 %

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol) and sodium hydride (0.406 g, 10.15 mmol) were added to N,N-dimethylformamide (30 mL) with stirring and under nitrogen. After 15 minutes the reaction was cooled in an ice bath and benzenesulfonyl chloride (1.295 mL, 10.15 mmol) was added. The reaction mixture was stirred in the ice bath for 30 min and then allowed to warm up to room temperature. Water (30 mL) was added and the precipitate collected by filtration to afford the title compound as an orange solid (4.8 g).
Reaction SMILES: CC1(C)[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH2:14][C@H:15]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>CO.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>[OH:3][CH2:4][C@@H:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:14][C@H:15]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCCCOC2)COC1(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCCCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 2,2-dimethyl-4-((R)-oxepan-3-ylmethyl)oxazolidine-3-carboxylate (160 mg, 0.51 mmol) in MeOH (10 mL) was added p-TSA (30 mg, 0.17 mmol) and stirred at rt for 2 h. TEA (1 mL) was added, followed by 1 drop of Boc2O. The reaction mixture was stirred for another 30 min. The solvent was removed under vacuum to give crude product tert-butyl (S)-1-hydroxy-3-((R)-oxepan-3-yl)propan-2-ylcarbamate, which was used for next step without further purification. MS ESI +ve m/z 296 (M+Na).