Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:15]=2)[O:10][C:9]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].[Na]>ClCCl>[C:1]([O:5]/[N:6]=[C:7]1\[CH:8]=[C:9]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:10][C:11]2[C:16]\1=[CH:15][CH:14]=[C:13]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:40]([CH3:39])(=[O:42])=[O:41])[CH:12]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#CCCO)ccc12
Reactant: CS(=O)(=O)Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)O/N=c1\cc(-c2cc3ccccc3cn2)oc2cc(C#CCCOS(C)(=O)=O)ccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cold solution of 7-(4-Hydroxy-but-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (tert-butyl protected oxime of example 52) (200 mg, 0.485 mmol) and triethylamine (0.15 ml, 1.067 mmol) in dichloromethane (3 ml) was added dropwise methanesulfonyl chloride (75 μl, 0.970 mmol). The reaction mixture was stirred for 1.5 hours at 0° C. and poured onto a saturated solution of sodium hydrogenocarbonate. The product was extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated to dryness to yield methanesulfonic acid 4-{4-[(E)-tert-butoxyimino]-2-isoquinolin-3-yl-4H-chromen-7-yl}-but-3-ynyl ester. The methansulfonic ester was dissolved in dimethylformamide (4 ml) and treated with potassium carbonate (201 mg, 1.46 mmol) and methyl piperazine (73 mg, 0.728 mmol) and the mixture was stirred at 40° C. for 20 hours. The mixture was poured onto a saturated solution of sodium hydrogenocarbonate. The reaction mixture was extracted with dichloromethane, washed with water, brine, dried over sodium sulfate and absorbed over silica gel for purification by flash chromatography (gradient cyclohexane/dichloromethane: 0-45%) to yield 7-(but-3-en-1-ynyl)-2-Isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (156 mg, 82%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[C:51]([C:53]1([NH2:59])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)#[CH:52]>C(Cl)Cl>[C:51]([C:53]1([NH:59][C:18](=[O:19])[CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)#[CH:52]
Reactant: C#CC1(N)CCCCC1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC1(NC(=O)C(CCN2CCN(c3ccccc3OC)CC2)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.772 g, 5 mmole), triethylamine (1.518 g, 15 mmole), and N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which 1-ethynylcyclohexylamine (0.668 g, 6 mmole) was added at once at 0° C. The reaction mixture was stirred at room temperature overnight, washed with water (2×100 mL), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by trituration from diethyl ether/hexane gave 0.72 g of the title compound as the 0.12 methylene chloride solvate, m.p. 127°-9° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[C:6]([CH:9]=3)[CH:7]=[O:8])=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=Cc1cc(I)ccc1OCCN1CCCC1
Product: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.50 g, 4.35 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (214 mg, 5.00 mmol).
Reaction SMILES: [H-].[Na+].[Cl-].[Cl:4][C:5]1[CH:6]=[C:7]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH2:32]1[O:42][C:35]2([CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[O:34][CH2:33]1.O>CS(C)=O>[Cl:11][C:9]1[CH:8]=[C:7]([CH:12]=[C:38]2[CH2:39][CH2:40][C:35]3([O:42][CH2:32][CH2:33][O:34]3)[CH2:36][CH2:37]2)[CH:6]=[C:5]([Cl:4])[CH:10]=1
Reactant: Clc1cc(Cl)cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1cc(Cl)cc(C=C2CCC3(CC2)OCCO3)c1
Temperature: 90 °C
Yield: 32.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 4.2 grams (0.11 mole) of sodium hydride (60% in mineral oil) in 200 mL of anhydrous dimethyl sulfoxide was heated to about 90° C. where it was maintained for 10 minutes. After this time the reaction mixture was cooled to 25° C., and 46.0 grams (0.10 mole) of 3,5-dichlorophenylmethyltriphenylphosphonium chloride was added, followed by 14.0 grams (0.10 mole) of 1,4-cyclohexanedione mono-ethylene ketal. Upon completion of addition the reaction mixture was again warmed to 90° C., then it was allowed to cool to ambient temperature. After this time the reaction mixture was poured into 400 mL of water, and the mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were then washed with two 100 mL portions of water. The organic layer was concentrated under reduced pressure to an oily solid residue. The oily solid was taken up in a solution of 90 mL of petroleum ether and 10 mL of diethyl ether, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using 10% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 9.7 grams of 8-(3,5-dichlorophenylmethylene)-1,4-dioxaspiro[4.5]decane, mp about 66° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[CH:22]([NH:21][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=13)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccccc3)nc12
Yield: 51 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-4-carboxamide was prepared from 2-phenylbenzoxazole-4-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 51% yield as an off-white solid: mp 77-80° C.; 1H NMR (500 MHz, CDCl3) δ 9.58 (d, J=7.1 Hz, 1H), 8.24 (d, J=5.2 Hz, 2H), 8.19 (d, 1H, J=6.8 Hz, 1H), 7.72 (d, J=7.1 Hz, 1H), 7.61-7.49 (m, 3H), 7.48 (t, J=7.9 Hz, 1H), 4.31 (m, 1H), 3.51 (dd, J=7.1, 2.3 Hz, 1H), 3.10 (m, 2H), 2.91 (m, 2H), 2.83 (dd, J=10.1, 4.2 Hz, 1H), 2.16 (m, 1H), 2.05 (m, 1H), 1.65-1.43 (m, 3H); MS (APCI) m/z 348 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[OH:10]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Reaction time: 18 h
Yield: 107.3 %

Procedure:
To 20 g of (2-amino-5-chlorophenyl)(2-chlorophenyl)methanone dissolved in 80 ml of ethanol are introduced portionwise 8.6 g of sodium borohydride, and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 21.63 g of the expected product.
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:36]=[CH:37][C:38]=1[CH2:39][O:40]C(=O)C1C=CC=CC=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:34][CH3:35])=[C:20]([C:22]([CH2:32][CH3:33])=[CH:23][CH:24]=[CH:25][C:26]([CH2:30][CH3:31])([OH:29])[CH2:27][CH3:28])[CH:21]=1)(=O)C1C=CC=CC=1.[Cl-].[NH4+]>C(=O)([O-])[O-].[K+].[K+].CO>[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:36]=[CH:37][C:38]=1[CH2:39][OH:40])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:34][CH3:35])=[C:20](/[C:22](/[CH2:32][CH3:33])=[CH:23]/[CH:24]=[CH:25]/[C:26]([CH2:27][CH3:28])([OH:29])[CH2:30][CH3:31])[CH:21]=1
Reactant: CCC(=CC=CC(O)(CC)CC)c1cc(OCc2ccc(COC(=O)c3ccccc3)c(COC(=O)c3ccccc3)c2)ccc1OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC/C(=C\C=C\C(O)(CC)CC)c1cc(OCc2ccc(CO)c(CO)c2)ccc1OC
Reaction time: 5 h

Procedure:
581 mg of 7-[5-(3,4-bis-benzoyloxymethylbenzyloxy)-2-methoxyphenyl]-3-ethylnona-4,6-dien-3-ol (0.89 mmol) are dissolved in 20 ml of a 2% potassium carbonate solution in methanol and then the reaction medium is stirred for 5 hours. After treating with a saturated ammonium chloride solution and extracting with ethyl acetate, the organic phases are combined, dried and concentrated under reduced pressure. The residue is purified by chromatography on a silica column. A yellow oil is obtained (m=284 mg; Y=72%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][C@@H:46]([NH:55][C:56]2[CH:61]=[CH:60][C:59]([S:62]([NH2:65])(=[O:64])=[O:63])=[CH:58][C:57]=2[S:66]([C:69]([F:72])([F:71])[F:70])(=[O:68])=[O:67])[CH2:47][S:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:40][CH2:39]1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([NH:65][S:62]([C:59]3[CH:60]=[CH:61][C:56]([NH:55][C@H:46]([CH2:45][CH2:44][N:41]4[CH2:42][CH2:43][O:38][CH2:39][CH2:40]4)[CH2:47][S:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:57]([S:66]([C:69]([F:71])([F:72])[F:70])(=[O:68])=[O:67])[CH:58]=3)(=[O:63])=[O:64])=[O:22])=[CH:23][CH:24]=2)[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Yield: 33.3 %

Procedure:
The title product (71.4 mg, yield: 33%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 33. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 106.7 mg, 0.2 mmol) and (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 117 mg, 0.21 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, 4 g silica gel column, eluting with 0→100% EtOAc/hexanes), providing the title product.
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]#[CH:3])=[CH:6][CH:7]=1)#[N:12]
Reactant: CC(C)(O)C#Cc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C#Cc1ccc(C#N)cc1
Reaction time: 4 h
Yield: 61.4 %

Procedure:
23.5 g of 3-methyl-1-(4'-cyanophenyl)-1-butyn-3-ol was dissolved in 250 ml of toluene in nitrogen atmosphere, and 1.6 g of sodium hydride (60% in paraffin liquid) was added thereto. This was stirred for 4 hours at 80° to 90° C. The reaction solution was poured into 300 ml of water, extracted with chloroform, and washed three times with water. Toluene and chloroform were removed by distillation, and the residue was recrystallized from methanol to obtain 9.9 g of 4-cyanophenylacetylene.
Reaction SMILES: [OH:1][C@H:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C@@H:4]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:3]1.O[C@@H]1C(C)(C)CC[C@H](N2C(=O)C3C(=CC=CC=3)C2=O)C1.O.NN.[ClH:44].Cl.N[C@H]1C[C@@H](O)C(C)(C)CC1>C(O)C>[ClH:44].[NH2:10][C@@H:4]1[CH2:3][C@H:2]([OH:1])[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5]1
Reactant: CC1(C)CC[C@@H](N2C(=O)c3ccccc3C2=O)C[C@H]1O
Agent: CC1(C)CC[C@@H](N)C[C@H]1O
Agent: CC1(C)CC[C@H](N2C(=O)c3ccccc3C2=O)C[C@@H]1O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)CC[C@H](N)C[C@@H]1O
Temperature: 25 °C
Yield: 115 %

Procedure:
To a mixture of 2-((1R,3R)-3-hydroxy-4,4-dimethylcyclohexyl)isoindoline-1,3-dione and 2-((1S,3S)-3-hydroxy-4,4-dimethylcyclohexyl)isoindoline-1,3-dione (1.1 g, 4.02 mmol) in ethanol (50 mL) was added hydrazine hydrate (0.195 mL, 4.02 mmol). The resulting solution was allowed to stir at reflux overnight under a nitrogen atmosphere. The reaction was cooled to ambient temperature and then the pH was adjusted to <2 via addition of concentrated aqueous hydrochloric acid. The precipitate was filtered off, rinsed with ethanol, and then the resulting filtrate was concentrated to 20 mL under reduced pressure. An equal volume of water was added and this mixture was stirred at ambient temperature for 15 min. The solids were filtered off, rinsed with water, and the filtrate was concentrated under reduced pressure to give a solid that was dried in a vacuum oven for a few hours to afford a mixture of (1R,5R)-5-amino-2,2-dimethylcyclohexanol hydrochloride and (1S,5S)-5-amino-2,2-dimethylcyclohexanol hydrochloride (835 mg, 4.65 mmol, 115% yield) that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87-8.21 (m, 3H), 2.98-3.23 (m, 1H), 2.75-3.02 (m, 1H), 1.49-1.92 (m, 2H), 1.26-1.47 (m, 3H), 0.96-1.16 (m, 1H), 0.48-0.93 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].C(N=C=NC(C)C)(C)C>O1CCCC1>[C:12]([CH2:14][C:15]([NH:4][C:3]1[CH:5]=[C:6]([O:10][CH3:11])[C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1])=[O:16])#[N:13]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#CCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
2,4-Dichloro-5-methoxyaniline (5.00 g, 26 mmol) and cyanoacetic acid (2.28 g, 26.8 mmol) were mixed in 50 mL of tetrahydrofuran until a solution formed. This solution was heated to reflux and 1,3-diisopropylcarbodiimide (4.2 mL, 26.8 mmol) was added dropwise. After 30 minutes the mixture was cooled to ˜15° C. in an ice-bath. The solid was collected by filtration and washed with tetrahydrofuran. The filtrate was slowly poured into water and stirred for 30 minutes. The white solid was collected by filtration, washed with water, and was then dissolved in 500 mL of ethyl acetate. The solution was dried over sodium sulfate and concentrated in vacuo to give 5.9 g (88%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide as a white solid, mp 180-181° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 4.02 (s, 2H), 7.58 (s, 1 H), 7.66 (s, 1 H), 10.00 (s, 1 H); MS (ES) m/z257.0, 259.0 (M−H)−
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+:22]>CO>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O-:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:6]=1.[Na+:22]
Reactant: Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)[O-])cc1

Procedure:
To a solution of 300 mg. of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of methanol is added 1 molar equivalent of sodium hydroxide, in the form of a 0.1N solution. The solvent is then evaporated under reduced pressure and the residue taken up in 2 ml. of methanol, followed by precipitation with ether, to yield crude sodium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate which can be crystallized from ethyl acetate-hexane.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[CH2:6][CH:5]2[CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:10]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CC(N(C)C)=O.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.CCOC(C)=O>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[CH2:6][CH:5]2[CH2:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])[CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cc(I)cc1c32
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cc(-c4ccc(Cl)cc4Cl)cc1c32
Temperature: 66 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
A mixture of (rac)-2-[(8-iodo-2,3,5,6-tetrahydro[1,4]oxazino[2,3,4-hi]indol-6-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.044 g, 0.098 mmol), 2,4-dichlorophenylboronic acid (0.028 g, 0.147 mmol), tetrakis(triphenylphosphine)palladium (0.011 g, 0.01 mmol) and K2CO3 (0.054 g, 0.39 mmol) in THF-DMA (1:1, 2.0 mL) was heated at 66° C. for 2 h. 2,4-Dichlorophenylboronic acid (0.02 g, 0.105 mmol), tetrakis(triphenyl-phosphine)palladium (0.007 g, 0.006 mmol) and K2CO3 (0.02 g, 0.145 mmol) were added and heat was continued for 24 h. 2,4-Dichlorophenylboronic acid (0.02 g, 0.105 mmol) and tetrakis(triphenyl-phosphine)palladium (0.007 g, 0.006 mmol) were again added and heat was continued for another 3 h. After cooling down to rt, water (10.0 mL) and EtOAc (10.0 mL) were added and separated. The aqueous layer was extracted with EtOAc (2×). The combined EtOAc solution was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to prep TLC (EtOAc/hexane, 1:2) to give 0.015 g (32%) of colorless solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.92-7.90 (m, 2 H), 7.81-7.78 (m, 2 H), 7.45 (d, J=2.0 Hz, 1 H), 7.27-7.18 (m, 2 H), 6.80 (s, 1 H), 6.74 (s, 1 H), 4.51-4.47 (m, 2 H), 4.13-4.09 (m, 1 H), 4.03-3.97 (m, 1 H), 3.83-3.79 (m, 1 H), 3.46-3.42 (m, 1 H), 3.38-3.35 (m, 1 H), 3.23-3.19 (m, 1 H), 3.16-3.14 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:21][CH3:22])=[C:13]([O:16]C(OC)=O)[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:21][CH3:22])=[C:13]([OH:16])[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:41])([F:40])[F:42])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC(=O)OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1c2cc(O)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 12 h
Yield: 50.3 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-7-methoxycarbonyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (5.0 g, 8.0 mmol) and potassium carbonate (2.2 g, 16 mmol) in methanol (45 mL) was stirred at room temperature. After 12 hours, water (100 mL) was added, and the volatiles were removed in vacuo. The mixture was then extracted with ethyl acetate (3×100 mL), the combined organic extracts were washed with saturated sodium bicarbonate solution (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 4.67 g of crude product. Purification by silica gel chromatography using 0-25% ethyl acetate/hexanes as eluent afforded 2.27 g of the title compound (50%). MS m/z 566 (M++2), 583 (M++19); 1H NMR (CDCl3) δ7.07 (C8, s, 1H), 6.36 (C5, s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:23])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.O>CN(C=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:23][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[NH:11][N:10]=2)=[CH:33][CH:34]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2[nH]nc(OCc3ccc(F)cc3)c2-c2ccc(F)cc2)cc1
Reaction time: 0.75 h
Yield: 80 %

Procedure:
A mixture of 4-(4-fluorophenyl)-3-hydroxy-5-(4-(methylsulphonyl)phenyl)-pyrazole [(366 mg, 1.1 mmol), prepared according to the method of Example 5C, K2CO3 (152 mg, 1.1 mmol) in DMF (20 mL) at 50° C. was treated dropwise with a solution of 1-(bromomethyl)-4-fluorobenzene (0.141 mL, 1.1 mmol) in DMF (5 mL), and the mixture was stirred for 45 minutes. The reaction mixture was then poured into water and extracted with ethyl acetate. The acetate extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide 3-(4-fluorobenzyloxy)-4-(4-fluorophenyl)-5-(4-(methyl-sulphonyl)phenyl)pyrazole (yield: 325 mg; 80%). MS (APCI+) m/z 441 (M+H)+; (APCI−) m/z 475 (M+Cl)−; 1H NMR (300 MHz, DMSO-d6) δ3.26 (s, 3H), 5.28 (s, 2H), 7.19 (m, 3H), 7.25 (m, 3H), 7.48 (m, 2H), 7.57 (d, J=9 Hz, 2H), 7.94 (d, J=9 Hz, 2H).
Reaction SMILES: [C:1]1([NH:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH3:20])=C(Cl)[N:12]=1>>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH3:20])=[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccccc1
Product: Cn1cnc2c(Nc3ccccc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-phenyl-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=3)=[CH:12][C:11]([C:23]([O:25]CC)=[O:24])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=3)=[CH:12][C:11]([C:23]([OH:25])=[O:24])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(OC)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: COc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Reaction time: 6 h

Procedure:
The preparation of the title compound takes place starting from the compound of Example 42A in analogy to the synthesis of the compound of Example 71A but with stiffing for 6 hours. 1.38 g of the title compound are obtained.