Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C:23]3=[O:31])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][C:23]4=[O:31])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
A solution of 1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one (1 eq) in dry CH2Cl2 was treated with methanesulfonyl chloride (1.1 eq) and triethylamine at RT for 15 h. Quenching with H2O and extraction into CH2Cl2 followed by concentration and purification by prep HPLC gave the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].Cl.[OH:51][N:52]=[C:53]1[CH2:58][CH2:57][N:56]([C:59](=[NH:62])[CH2:60][SH:61])[CH2:55][CH2:54]1>C(#N)C.CS(C)=O.O1CCCC1.O.P([O-])([O-])([O-])=O.[C].[Pd].CCOCC>[OH:51][N:52]=[C:53]1[CH2:54][CH2:55][N:56]([C:59](=[NH:62])[CH2:60][S:61][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([OH:37])=[O:36])[CH2:57][CH2:58]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: N=C(CS)N1CCC(=NO)CC1
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCC(=NO)CC3)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
0.21 ml of diisopropylethylamine and 0.22 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 363 mg of p-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 5 ml of anhydrous acetonitrile, and the mixture was stirred for one hour with ice-cooling. A solution of 0.18 ml of diisopropylethylamine and 324 mg of 2-(4-hydroxyiminopiperidin-1-yl)-2-iminoethylmercaptan hydrochloride in 3 ml of dimethylsulfoxide was then added dropwise to the mixture, which was stirred for a further 20 minutes with ice-cooling. The reaction mixture was then poured into 100 ml of anhydrous ether, and the solvent was decanted off from the gummy material which formed. This material was dissolved in a mixture of 20 ml of tetrahydrofuran, 7 ml of water and 23 ml of 0.1M phosphate buffer (pH 7.0), and the solution was subjected to catalytic hydrogenation at room temperature for 4 hours in the presence of 0.3 g of 10% palladium-carbon. The hydrogenated solution was filtered over "Celite" (Trade Mark) filter aid, the filtrate was extracted with 200 ml of ether, and the aqueous layer was concentrated under reduced pressure. The concentrate was subjected to chromatography using a 300 ml column of "Dowex 50W" (Trade Mark) cation exchange resin (Na+ type), and 27 mg of the title compound were obtained from the fraction eluted with water.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(OCC(C)=C)O[C:37]([CH3:40])([CH3:39])[CH3:38]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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]>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:39][C:37]([CH3:40])=[CH2:38])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([N:20]([C:21]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:27])[C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Reactant: C=C(C)COC(=O)OC(C)(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 55 °C
Yield: 92.1 %

Procedure:
To a solution of tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (3.59 g, 7.49 mmol, 1.00 equiv) in THF (75 ml) was added tert-butyl (2-methylallyl) carbonate (2.58 g, 15.0 mmol, 2.00 equiv). This solution was degassed by placing under vacuum and backfilling with N2 (3×). To this solution were added dppf (0.830 g, 1.50 mmol, 0.200 equiv) and Pd2 dba3 (0.686 g, 0.749 mmol, 0.100 equiv). The resulting dark solution was heated to 55° C. (external temp) for 1 h, and then cooled to room temperature. The solution was concentrated and purified by automated silica gel column chromatography (4-16% acetone in hexanes) to provide tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-9-methyl-8-(2-methylallyloxy)-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (3.68 g, 92%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.22-7.12 (m, 3H), 5.12 (dd, J=8.5, 6.6 Hz, 1H), 5.07-4.98 (m, 1H), 4.98-4.83 (m, 2H), 4.15-4.02 (m, 2H), 3.95 (d, J=11.8 Hz, 1H), 3.86 (dd, J=11.8, 8.5 Hz, 1H), 3.52 (d, J=10.7 Hz, 1H), 3.40 (dd, J=10.9, 6.0 Hz, 1H), 3.23 (t, J=8.8 Hz, 1H), 3.11 (dd, J=13.6, 3.3 Hz, 1H), 2.40 (t, J=12.5 Hz, 1H), 2.01 (d, J=5.6 Hz, 1H), 1.77 (s, 3H), 1.54-1.39 (m, 21H); 13C NMR (101 MHz, CDCl3) δ 169.97, 152.62, 141.78, 140.01, 129.25, 128.33, 126.02, 112.13, 84.93, 83.01, 75.89, 75.20, 70.96, 57.44, 47.00, 35.02, 27.92, 19.79, 18.97; ESIMS (m/z) 556.8 ([M+Na]+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=C=O)=[CH:42][CH:41]=1>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([NH:46][C:43]4[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=4)=[O:7])[CH2:13][CH2:12]3)=[CH:15][C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Reactant: O=C=Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloroquinoline-2-carboxylate (1.0 g, 2.4 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (5 mL). After 1 h at room temp., the reaction mixture is adjusted to pH 10–11 with 10% aq. NaOH and extracted with EtOAc. The combined extracts are dried (Na2SO4) and concentrated. The residue is dissolved in CH2Cl2 (70 mL) and treated with 4-fluorophenyl isocyanate (0.32 mL, 2.8 mmol) for 15 h at room temp. The reaction mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography with CH2Cl2-MeOH yielding the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[C:19]([C:21]1[N:25]([CH3:26])[C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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]>[C:19]([C:21]1[N:25]([CH3:26])[C:24]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCCNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1C(F)(F)F
Reaction time: 16 h
Yield: 32.7 %

Procedure:
According to general procedure B, 4-bromo-N-propyl-2-(trifluoromethyl)benzenesulfonamide (193 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethyl)benzenesulfonamide (68 mg, 33%) was provided after purification. MS (ESI) m/z 371. HPLC purity 100.0% at 210-370 nm, 10.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)C(C)C)(C)C>O1CCCC1.O.CCOC(C)=O>[C:36]([O:35][C:33](=[O:34])[CH2:32][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(N)c4)sc3n2)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNc1cccc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)c1
Temperature: 120 °C

Procedure:
To a solution of tert-butyl 4-(2-(3-aminophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (50 mg, 0.117 mmol, 1.0 equiv) in 1.0 mL tetrahydrofuran is added dropwise a solution of tert-butyl bromoacetate (0.069 mL, 0.467 mmol, 4.0 equiv) in 0.5 mL tetrahydrofuran and a solution of N,N-diisopropylethylamine (0.082 mL, 0.467 mmol, 4.0 equiv) in 0.5 mL tetrahydrofuran. The mixture is heated in a microwave reactor for 30 min at 120° C. Upon completion, the mixture is taken up in water and EtOAc. The layers are separated and the aqueous layer is back-extracted with EtOAc. The combined organic extracts are washed with water and brine, and concentrated in vacuo to give crude tert-butyl 4-(2-(3-(2-tert-butoxy-2-oxoethylamino)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate as a yellow solid. The residue is then taken on crude to the next reaction, which followed the same deprotection procedure as above to give 2-(3-(5-oxo-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)phenylamino)acetic acid (18 mg, 40%) as a tan solid.
Reaction SMILES: N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH:16]=1.Br[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>C(Cl)(Cl)Cl.[Cu](I)I.CO.O1CCOCC1>[CH:34]1[C:35]2[C:30](=[CH:29][CH:28]=[CH:37][CH:36]=2)[CH:31]=[CH:32][C:33]=1[N:23]1[CH2:24][CH2:25][N:21]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[C:22]1=[O:26]
Reactant: Brc1ccc2ccccc2c1
Reactant: O=C1NCCN1c1cccnc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1N(c2cccnc2)CCN1c1ccc2ccccc2c1
Temperature: 110 °C
Yield: 27.2 %

Procedure:
Copper iodide (10.0 mg, 0.113 mmol), trans-1,2-diamino cyclohexane (10.0 mg, 0.091 mmol) and potassium carbonate (169 mg, 1.22 mmol) were added to a solution of 1,4-dioxane (5 mL) previously purged with argon (10 minutes). The reaction mixture was purged with argon for 10 minutes, followed by the addition of 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 100 mg, 0.61 mmol) and 2-bromo naphthalene (126 mg, 0.61 mmol). The reaction mixture was heated to reflux at 110° C. for 15 hours. The reaction was monitored by TLC (10% MeOH in chloroform). The reaction mixture was filtered through a celite bed and the bed was washed with chloroform. The organic layer was concentrated and purification by column chromatography (using silica gel of mesh size of 60-120, 20% ethyl acetate in hexane as eluent) afforded 48 mg (28% yield) of 1-naphthalen-2-yl-3-pyridin-3-yl-imidazolidin-2-one.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]CC4C=CC=CC=4)[CH:16]=3)[CH:11]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[C:1]1([S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[CH:11]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1
Yield: 67.9 %

Procedure:
A mixture of 2-benzenesulfonyl-6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.043 g, 0.08 mmol), ammonium formate (0.096 g, 1.52 mmol), and 20% Pd(OH)2/C (0.025 g) in MeOH (10 ml) was refluxed under N2 for 1 hr, then filtered through Celite. The filtrate was evaporated in vacuo to a white residue that was dissolved in CH2Cl2 (10 ml) and washed with 1M NaOH (5 ml). The aqueous layer was extracted with CH2Cl2 (3×10 ml), and all of the combined organic solutions were dried over MgSO4 and concentrated in vacuo to give 0.026 g (72% yield) of colorless residue.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCCCC)CCC.CO>[NH2:9][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:2]([CH3:10])[CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [Li]c1ccccc1
Reactant: CN(C)C1(C#N)CCCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: CN(C)C1(C(N)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(dimethylamino)cyclopentanecarbonitrile D1 (4 g; 28.9 mmol) in THF (30 ml) at −70° C. under argon was added dropwise a solution of phenyllithium in dibutylether (17.7 ml of a 1.8M solution; 32 mmol). The reaction mixture was allowed to warm to room temperature over 3 h., recooled to 0° C. and methanol added (30 ml) followed by careful addition of sodium borohydride (3.3 g; 87 mmol). After stirring at room temperature for 18 h, the reaction mixture was cooled to 0° C. and saturated aqueous sodium bicarbonate added. The organic phase was evaporated and the resulting slurry extracted three times with DCM (3×150 ml). The combined extracts were dried (Na2SO4), and evaporated to afford the crude product as a yellow oil (6.8 g). Half of the crude product was chromatographed on silica gel eluting with DCM-methanol (9/1) and DCM-2M ammonia in methanol mixtures (95/5 to 9/1 to 8/2) to afford the title product as a colourless oil (2.3 g). This oil was dissolved in diethyl ether (20 ml) and hydrogen chloride in diethylether was added at 0° C. After 20 min, the suspension was filtered to give the dihydrochloride salt (2.8 g) of the title product as a white solid. 1H NMR (DMSO) δ: 1.25 (2H, bs), 1.36 (2H, bs), 1.66-2.13 (4H, m), 2.64 (3H, s), 2.79 (3H, s), 4.92 (1H, bs), 7.32 (3H, m), 7.54 (2H, m), 8.95 (3H, bs), 10.82 (1H, bs).
Reaction SMILES: C(N)CC1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1.[C:19]1([CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:47][CH:48]([Cl:52])[C:49](Cl)=[O:50]>O.C(Cl)Cl>[Cl:47][CH:48]([Cl:52])[C:49]([N:26]1[CH2:27][CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:50]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: c1ccc(C2NCCc3ccccc32)cc1
Agent: NCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: O=C(C(Cl)Cl)N1CCc2ccccc2C1c1ccccc1

Procedure:
By procedures described in Example 1 (Method A), phenethylamine and benzoyl chloride were converted to 1-phenyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 3.5 g of this isoquinoline compound, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 1.2 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 10 minutes, then water was added. The organic extract was dried with magnesium sulfate and stripped of solvent. The residue was recrystallized from ethanol to provide 4 g of a white cubic-crystal product having the elemental analysis reported in Table I.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>COC1C=CC(C2OC(C3C=CC(OC)=C(OC)C=3)CCC2)=CC=1OC>[C:11]([O:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1O
Agent: COc1ccc(C2CCCC(c3ccc(OC)c(OC)c3)O2)cc1OC
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 90 °C

Procedure:
0.0072 moles of salicylic acid and 0.029 moles acetic anhydride (molar ratio=1:4) were taken in a 20 ml reaction vessel of reaction station. Nano-crystalline sulfated zirconia catalyst (SZ-1), activated at 450° C. in static air with salicylic acid to catalyst weight ratio 10:1, was added and the mixture was heated at 90° C. for 240 minutes. The reaction mixture was filtered to separate the catalyst. The acetyl salicylic acid was crystallized from the reaction mixture. The crude yield of acetyl salicylic acid was 73%. It was further re-crystallized with ethanol-water to obtain pure crystals of acetyl salicylic acid.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:23](OC)=[O:24]>C(O)C>[O:24]=[C:23]1[C:14]2[N:15]=[N:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]=2[NH:2][N:1]1[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: COC(=O)c1nnc2ccccc2c1Cl
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCO
Product: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 47.5 °C
Reaction time: 1 h

Procedure:
4-Hydrazinobenzoic acid (68.4 mg, 0.45 mmol) was mixed at room temperature with ethanol (5 ml) to give a creme-coloured suspension. Methyl 4-chlorocinnoline-3-carboxylate (100 mg, 0.45 mmol) was added and the mixture was heated to 45-50° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. Ethyl acetate (10 ml) was added to the residue. The mixture was stirred at room temperature for 1 h. The solids were collected by filtration and dried under vacuum. The title compound was isolated as a brown powder (120 mg, 0.39 mmol, 86%). LCMS: m/z 307 [M+H]+. NMR [DMSO-d6]: δ=7.69-7.77 (m, 1 Haryl); 7.81-7.90 (m, 2 Haryl); 8.05 (d, J=8.85, 2 Haryl); 8.20 (d, J=7.92 Hz, 1 Haryl); 8.33 (d, J=8.85 Hz, 2 Haryl); 14.64 (s, NH).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH2:17]([C:19]1[O:20][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:22]([C:24](O)=[O:25])[N:23]=1)[CH3:18]>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:24]([C:22]3[N:23]=[C:19]([CH2:17][CH3:18])[O:20][C:21]=3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:25])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CCc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-ethyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH2:36][OH:37])[CH2:31]3)[CH:7]=2)[CH2:3][CH2:2]1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH3:41])[C@@H:32]([CH2:36][OH:37])[CH2:31]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](CO)C3)c2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN(C)[C@@H](CO)C3)c2c1
Reaction time: 4 h
Yield: 85.2 %

Procedure:
The product of Example 85 (80 mg) was dissolved in dichloromethane (10 mL). Formaldehyde (0.057 mL) and sodium triacetoxyborohydride (98 mg) were then added and the mixture stirred for 4 hours. Water (10 mL) was then added and the mixture extracted with dichloromethane (30 mL). The organics were combined and evaporated under reduced pressure. The residue was purified by HPLC to give the title compound as a solid (70 mg).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]([OH:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:20]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2-c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and biphenyl-2-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C24H24O5 [M+Na]+: 415.4.