Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:47]([CH3:49])[CH3:48])[C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:24][CH:23]=3)=[C:19]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH:43]([CH3:45])[CH3:44])[S:18][C:17]=2[CH:46]=1)=[O:11])=O)(C)(C)C.[ClH:50]>>[ClH:50].[NH2:8][C@@H:9]([CH:47]([CH3:49])[CH3:48])[C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:20]([O:21][C:22]3[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)=[C:19]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH:43]([CH3:44])[CH3:45])[S:18][C:17]=2[CH:46]=1)=[O:11]
Reactant: CC(C)c1ccccc1-c1sc2cc(OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Oc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CC(C)c1ccccc1-c1sc2cc(OC(=O)[C@@H](N)C(C)C)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Yield: 85 %

Procedure:
A solution of (S,E)-3-(4-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)phenoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-6-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (106.8 mg, 0.156 mmol) in HCl (2.0 mL, 4N in 1,4-dioxane) was stirred at room temperature for 18 hours after which time the mixture was concentrated in vacuo to remove HCl and 1,4-dioxane. The resulting crude material was then triturated with heptane (2×) to obtain (S,E)-3-(4-((6-((2-amino-3-methylbutanoyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid hydrochloride (54.1 mg, 0.094 mmol, 85% yield). 1H NMR (400 MHz, CD3OD) δ ppm=7.81 (d, J=2.02 Hz, 1H), 7.42-7.62 (m, 4H), 7.25-7.42 (m, 3H), 7.09-7.26 (m, 2H), 6.86 (d, J=8.59 Hz, 2 H), 6.32 (d, J=15.66 Hz, 1 H), 4.29 (d, J=5.05 Hz, 1H), 3.18 (s, 1 H), 2.44-2.60 (m, 1 H), 1.12-1.35 (m, 12H) HRMS (m/z, MH+): 530.1988.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cccnc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-3-boronic acid. The title compound (24 mg) was isolated as the hydrochloride salt which was an off-white solid, m/z 342 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[S:22](=[O:24])(=[O:23])[N:21](C(OC)=O)[CH2:20][CH2:19][CH:18]3[CH3:29])=[C:12]([F:30])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH:18]([CH3:29])[CH2:19][CH2:20][NH:21][S:22]3(=[O:24])=[O:23])=[C:12]([F:30])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)N1CCC(C)N(Cc2ccc(N3CCN(C(C)=O)CC3)cc2F)S1(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CN3C(C)CCNS3(=O)=O)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of methyl 6-{[4-(4-acetylpiperazin-1-yl)-2-fluorophenyl]methyl}-5-methyl-1,1- dioxo-1λ6,2,6-thiadiazinane-2-carboxylate (420 mg, 0.95 mmol) and NaOH (76 mg, 1.90 mmol) in MeOH/H2O (1:1, 10 mL) was stirred at 0° C. for 10 minutes and ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (1% (NH4)2CO3) to afford 2-{[4-(4-acetylpiperazin-1-yl)-2-fluorophenyl]methyl}-3-methyl-1λ6,2,6-thiadiazinane-1,1-dione as white solid (300 mg, 82%). 1H NMR (500 MHz, CDCl3) δ 7.42 (t, 1H), 6.68 (dd, 1H), 6.54 (dd, 1H), 4.373 (d, 1H), 4.22 (d, 1H), 3.85-3.90 (m, 1H), 3.76 (t, 2H), 3.61 (t, 2H), 3.53 (dd, 2H), 3.14-3.20 (m, 4H), 2.14 (s, 3H), 1.58-1.67 (m, 2H), 1.23 (d, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH2:5][O:4][CH2:3][C:2]1=2.[C:7]1([C@H:13]([NH2:15])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Al](C)C>>[C:7]1([CH:13]([NH:15][CH:3]2[CH:2]([OH:1])[CH2:6][CH2:5][O:4]2)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1OCC2=C1O2
Reactant: C[C@@H](N)c1ccccc1
Agent: C[Al](C)C
Product: CC(NC1OCCC1O)c1ccccc1

Procedure:
According to the procedure of Overman, et al. (J. Org. Chem. 1985, 50, 4154), 3,4-epoxy-2,5-dihydrofuran was treated with (R)-1-phenylethylamine and trimethylaluminum to give a 1:1 mixture of diastereomers. The mixture was purified by silica gel chromatography to provide the desired compound.
Reaction SMILES: Cl[C:2]1[CH:3]=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CC(O)C>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH:2]([CH3:3])[CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cccc2[nH]c(C(=O)OC(C)C)c(Sc3ccc(Cl)cc3)c12
Yield: 53 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.21 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with 2-propanol (2 mL) provided 40 mg (53%) of product 13 as a white solid, mp 190-192° C. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=6 Hz, 6H), 2.60 (s, 3H), 5.05-5.14 (m, 1H), 6.88 (d, J=8 Hz, 1H), 6.98 (d, J=9 Hz, 2H), 7.23 (t, J=8 Hz, 1H), 7.30 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 1H), 12.45 (s, 1H). LC-MS (CI): m/z 360.1 [(M+H)+ C19H18ClNO2S requires 359.07]. Purity (100%). Calcd for C19H18ClNO2S.0.07CH2Cl2: C, 62.61; H, 5.00; N, 3.83; S, 8.77; Cl, 11.05. Found: C, 62.32; H, 5.01; N, 3.77; S, 9.08; Cl, 10.93.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CO[C:11]1[CH:12]=[CH:13][CH:14]=[C:15](OC)[C:16]=1[C:17]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Br[C:39]1[N:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.B1(CC2C=CC=CC=2)C2CCCC1CCC2>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([C:39]1[N:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: Oc1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc(Cc2ccccc2)nc1
Temperature: 80 °C

Procedure:
In a sealed tube, a mixture of K3PO4 (16 g, 78 mmol), S-Phos (0.64 g, 1.6 mmol), and palladium acetate (0.29 g, 1.3 mmol) in THF (70 mL) was treated with 6-bromopyridin-3-ol (4.50 g, 26 mmol) and β-benzyl-9-BBN (0.5M solution in THF, 103 mL, 52 mmol). The mixture was heated to 80° C. for 18 h and diluted with EtOAc. The organic phase was washed with 2M aqueous NaOH, brine, dried over MgSO4, and concentrated. Purification by flash chromatography using EtOAc/hexanes gave 6-benzylpyridin-3-ol. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.66 (br. s, 1H), 8.03 (t, J=1.8 Hz, 1H), 7.13-7.30 (m, 4H), 7.07 (d, J=1.9 Hz, 2H), 3.95 (s, 2H). MS (ESI) m/z: Calculated; 185.1 Observed: 186.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH:21][C:4](=[O:6])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: NNc1ccccc1F
Reactant: Nc1cccc(F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Nc1cccc(F)c1C(=O)NNc1ccccc1F
Temperature: -12 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
2-Amino-6-fluorobenzoic acid (2.00 g, 12.89 mmol) was combined with 2-fluorophenylhydrazine hydrochloride (2.096 g, 12.89 mmol) and HOBt (3.949 g, 25.79 mmol) in dry THF (75 ml) and cooled to about −12° C. N-Methylmorpholine (2.835 ml, 25.79 mmol) was added, the mixture was stirred for 5 minutes, then EDC hydrochloride (2.66 g, 13.88 mmol) was added. The mixture was maintained at a temperature between −14 and −10° C. for 1 hour, then allowed to slowly warm to room temperature and stirred for 18 hours. The mixture was cooled to 0° C., then filtered through CELITE® (diatomaceous earth). The filtrate was diluted with EtOAc, treated with saturated NaHCO3 and the layers separated. The organic layer was washed twice with 50% saturated NaHCO3 and then dried over MgSO4 and concentrated. The resulting solid was triturated with dichloromethane, filtered, rinsed with a very small amount of dichloromethane and dried. The filtrate from the trituration was re-triturated with a small amount of dichloromethane, filtered, rinsed with a tiny amount of dichloromethane and dried. The filtrate was concentrated to dryness, triturated with a small amount of Et2O, filtered, rinsed with a tiny amount of ether and dried. The three solids were combined to afford a total of 2.182 g (64%) of 2-amino-6-fluoro-benzoic acid N′-(2-fluoro-phenyl)-hydrazide (Intermediate 44) as an off-white solid. MS (APCI): (M−1)=262.0.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[CH:9]1.C(Cl)(Cl)Cl.CO>C(O)=O.[Zn]>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Agent: [Zn]
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1=C(c2ccncc2)SCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.1 %

Procedure:
Zinc powder (1.7 g) was added to a solution of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (1g) in formic acid (14 ml) and the mixture was stirred at ambient temperature for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in water (30 ml), was adjusted to pH 7.0 by 1N aqueous sodium hydroxide, was extracted with chloroform and was dried over magnesium sulfate. Chloroform was removed and the residue was purified by the preparative thin layer chromatography [Merck TLC plate, silica gel 60F254 (supplied by Merck & Co. Inc., U.S.A.), 20×20 cm, thickness=1 mm, developing solvent; chloroform/methanol=20:1] to give the titled compound (0.2 g, yield 37.1%) as pale yellow plates. The physiocochemical properties were as described above.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:35]1[C:48]2[C:39](=[N:40][C:41]3[C:46]([C:47]=2[NH:49][C:50]2[CH:51]=[C:52]([CH2:57][OH:58])[CH:53]=[C:54]([NH2:56])[CH:55]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][CH:36]=1>>[CH:35]1[C:48]2[C:39](=[N:40][C:41]3[C:46]([C:47]=2[NH:49][C:50]2[CH:55]=[C:54]([NH:56][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH:53]=[C:52]([CH2:57][OH:58])[CH:51]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][CH:36]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)cc1C(=O)O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 66.8 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,4,5-trimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: [NH:1]([C:8]1[CH2:17][C:16]([C:18]([O:20]C)=O)=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][C:9]=1[C:10]([O:12]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH:26]1[CH:27]=[C:28]2[C:18]([C:16]3[C:15]([NH:22][C:23]2=[CH:24][CH:25]=1)=[CH:14][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:17]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])=[O:20]
Reactant: COC(=O)C1=C(Nc2ccccc2)CC(C(=O)OC)=C(Nc2ccccc2)C1
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Yield: 90.9 %

Procedure:
A suspension of 400 g of dimethyl 2,5-dianilino-3,6-dihydroterephthalate and 1 l of water was introduced by means of a two-material nozzle and 1.5 m3 of nitrogen into a tubular reactor at 590° C. In addition, a gas mixture of 400 l of air and 600 l of nitrogen was passed in at the side. 300 g of quinacridone having a purity of 97% were obtained.
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:3][C@@H:2]2[CH:4]=[CH:5][C@H:6]3[CH2:8][O:9][C@@H:1]2[O:7]3)=[O:35])=[CH:32][CH:31]=1
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1C=C[C@H]2CO[C@@H]1O2)c1ccc(Cl)cc1
Yield: 84.4 %

Procedure:
1.28 g (10.0 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose, 5.25 g (20.0 mmol) of triphenyl phosphine, and 3.13 g (20.0 mmol) of 4-chlorobenzoic acid were added to 16 ml of dry THF, and a solution obtained by dissolving 3.13 g (20.0 mmol) of diethylazodicarboxylate in 16 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 22 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column chromatograph (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:chloroform=4:1) to obtain 2.25 g (yield: 84.3%) of 1,6-anhydro-2-O-(4-chlorobenzoyl)-3,4-dideoxy-β-D-erythro-hex-3-enopyranose.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[CH:16]=[N+:17]([CH3:19])[CH3:18].ClC1C=C(C=CC=1)C=O.CNC>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([N:17]([CH3:19])[CH3:18])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: C[N+](C)=Cc1cccc(Cl)c1
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: O=Cc1cccc(Cl)c1
Agent: [Cl-]
Product: CN(C)C(c1cccc(Cl)c1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (3-chloro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 3-chloro-benzaldehyde and dimethylamine.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[CH3:6][O:7][CH2:8][CH:9]([NH:11][C:12]1[C:16]([CH3:17])=[CH:15][S:14][C:13]=1[CH3:18])[CH3:10].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1(C)C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>[CH3:18][C:13]1[S:14][CH:15]=[C:16]([CH3:17])[C:12]=1[N:11]([CH:9]([CH3:10])[CH2:8][O:7][CH3:6])[C:21](=[O:22])[CH2:20][Cl:19]
Reactant: COCC(C)Nc1c(C)csc1C
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: COCC(C)N(C(=O)CCl)c1c(C)csc1C

Procedure:
0.02 Mol thionylchloride in 5 ml toluene are added dropwise, within 40 minutes, to 0.02 mol N-(1-methoxyprop-2-yl-)-2,4-dimethyltetrahydrothien-3-ylidenimine, dissolved in 10 ml of toluene at 20° . The reaction mixture is stirred for 2 hours whereby the hydrochloride of N-(-1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene is obtained. Then are added 0.02 mol of chloroacetylchloride dissolved in 5 ml toluene. This mixture is heated during 1 hour at reflux, whereby HCl escapes. The title compound is obtained by column chromatography on silica gel with cyclohexane/ethyl acetate (8:2), b.p. 148°-150°/0.03 Torr.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=O)[CH2:6][CH:5]([CH2:10][CH3:11])[N:4]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH3:2].C([C@H]1N[C@@H](CC)CC2(OCCO2)C1)C.FC1C=CC(S(Cl)(=O)=O)=CC=1.CN(C(OC)OC)C.[NH:55]1[CH:59]=CC=[N:56]1.O.NN>>[CH2:1]([C@H:3]1[C:8]2[CH:59]=[N:55][NH:56][C:7]=2[CH2:6][C@@H:5]([CH2:10][CH3:11])[N:4]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CCC1CC(=O)CC(CC)N1S(=O)(=O)c1ccc(F)cc1
Agent: CC[C@@H]1CC2(C[C@H](CC)N1)OCCO2
Agent: COC(OC)N(C)C
Agent: NN
Solvent: O
Product: CC[C@@H]1Cc2[nH]ncc2[C@H](CC)N1S(=O)(=O)c1ccc(F)cc1

Procedure:
Prepared by treatment of 2,6-diethyl-1-(4-fluorophenylsulfonyl)piperidin-4-one, which was prepared by sulfonylation of compound 126 using 4-fluorobenzenesulfonyl chloride followed by deprotection as shown in Example 17, with DMF-DMA followed by pyrazole formation using hydrazine hydrate as shown in Example 15.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[CH:12]=[CH:11][NH:10][C:8]=2[N:9]=1.[CH3:13]I>C1COCC1.O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[CH:12]=[CH:11][N:10]([CH3:13])[C:8]=2[N:9]=1
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2cnc(Cl)nc21
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of NaH (106.6 mg, 2.67 mmol) in THF (5 mL) was added 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.54 mmol) at 0° C. and stirred for 30 minutes at the same temperature. CH3I (1.5 g, 10.2 mmol) was added at 0° C. and the combined mixture stirred for 3 h at 15° C. After TLC showed the reaction was complete, the mixture was diluted with water 20 mL) and extracted with ethyl acetate EA (2×20 mL) and the combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (254 mg, 47.4%) as colorless oil which was used in next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[O:16][C:17](=O)[C@H:18]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:19][C:20]1[C:21]([CH2:29]Cl)=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([N:1]2[CH2:29][C:21]3[C:22]4[CH:23]=[N:24][NH:25][C:26]=4[CH:27]=[CH:28][C:20]=3[CH2:19][C@@H:18]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])[C:17]2=[O:16])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1

Procedure:
4-Amino-1-N-Boc-piperidine (110 mg, 0.55 mmol) and 2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionic acid methyl ester (150 mg, 0.34 mmol) was converted into the title compound in a manner analogous to the preparation of [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-acetic acid methyl ester. Crude product was obtained as a dark foam in quantitative yield. Material was carried forward without further purification. 1H NMR (300 MHz, CDCl3): δ=8.05 (m, 1H), 7.35 (m, 6H), 7.15 (m, 1H), 6.27 (m, 1H), 5.28 (m, 1H), 5.15 (s, 2H), 4.87 (d, J=16.5, 1H), 4.63 (m, 1H), 4.47 (m, 1H), 4.24 (m, 1H), 3.99 (m, 1H), 3.49 (m, 1H), 3.04 (m, 1H), 2.83 (m, 2H), 2.63 (m, 1H), 1.90 (m, 1H), 1.74 (m, 2H), 1.58 (s, 9H). MS m/e (M−H)−=532.1.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[C@:6]3([CH3:15])[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[C:18]1(B(O)O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]1([C:2]2[CH:17]=[CH:16][C:5]3[C@:6]4([CH3:15])[C@@H:11]([CH2:12][CH2:13][C:4]=3[CH:3]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]4)[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Br)ccc12
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Yield: 69.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (500 mg, 1.70 mmol), tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.07 mmol), 1-napthylboronic acid (439 mg, 2.55 mmol), 2.4 mL of 2M sodium carbonate and 4 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (200 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-50% methanol/ethyl acetate eluent gradient) to give 405 mg (70%) of the title compound as a white solid. mp 247°-248°. FDMS: m/e=341. α[D]589 =+1.93 (c=1.04, methanol).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[CH:39][C:38]=1[OH:51])(=[O:36])[CH3:35].O[C@H:53]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69])[CH2:54][CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>C1COCC1>[C:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[CH:39][C:38]=1[O:51][C@@H:53]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69])[CH2:54][CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])(=[O:36])[CH3:35]
Reactant: Cc1ccccc1[C@@H](O)CCC(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(OCc2cccnc2)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccnc2)cc1O[C@H](CCC(=O)OC(C)(C)C)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.7 %

Procedure:
Diisopropyl azodicarboxylate (8 g) is added portionwise to a stirred solution of triphenylphosphine (10.5 g) in THF (100 mL) at 0° C. under nitrogen. Stirring is continued at 0° C. for 15 minutes. A solution of 2-acetyl-5-(3-pyridylmethoxy)phenol (4.5 g) and tert-butyl (S)-4-hydroxy-4-(2-methylphenyl)butanoate (4.9 g) in THF (100 mL) is added at such a rate that the temperature does not exceed 5° C. The reaction is allowed to warm to ambient temperature stirred for 16 hours, then concentrated in vacuo. The residue is partitioned between ethyl acetate (200 mL) and water (200 mL) and the organic phase dried over magnesium sulphate, filtered and concentrated in vacuo.The residue is purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and cyclohexane (1:1 v/v) then with ethyl acetate. Fractions homogeneous in the required product are combined and evaporated to give t-butyl (R)-4-(2-acetyl-5-(3-pyridylmethoxy)phenoxy)-4-(2-methylphenyl)butanoate (2 g).