Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH:18]=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.CO[C:23](C)(C)[CH3:24]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:16][CH2:17][CH:18]=[CH:23][CH3:24]
Reactant: COC(C)(C)C
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCCC=O)CC2)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: CC=CCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3.16 g of ethyl-triphenylphosphonium bromide in 50 ml of dry t-butyl methyl ether was treated with 960 mg of potassium t-butylate while gassing with argon at -10° C. and the mixture was stirred for a further 45 minutes at 0° C. Thereafter, the mixture was cooled to -20° C., treated within 5 minutes with a solution of 1.45 g of 4-[trans-4-(p-cyanophenyl)cyclohexyl]butyraldehyde (purity 90%) in 20 ml of t-butyl methyl ether and the mixture was stirred for a further 30 minutes while warming to room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of water, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave p-[trans-4-(4-hexenyl)cyclohexyl]benzonitrile (4Z: 4E=88:12) as a colourless oil. Additional low-pressure chromatography (0.5 bar) of this material on 140 g of silver nitrate-coated silica gel (prepared according to Example 2) with hexane/diethyl ether (vol. 3:1) yielded 750 mg of p-[trans-4-(4Z-hexenyl)cyclohexyl]benzonitrile. Two-fold recrystallization from methanol finally gave 468 mg of colourless crystals with m.p. (C-I) 27.4° C. and cl.p. (N-I) 4.5° C.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[S:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)N(C(N)=S)c1ccc2c(c1)OCO2
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N1C(=S)NC(c2ccccc2)c2cc3c(cc21)OCO3
Reaction time: 4 h

Procedure:
A solution of 30 grams of N-isopropyl-N-(3,4-methylenedioxyphenyl)thiourea, 27.6 mls. of benzaldehyde, and 2 mls. of methanesulphonic acid in 500 ml. of toluene is refluxed under a Dean Stark water separator for 4 hours, during which 2 ml. water is collected. The filtered solution is then evaporated to yield a powder. This product is recrystallized from dioxane and water to obtain 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinthione, m.p. 215°-218°C.
Reaction SMILES: [Si]([O:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:33])[N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:18][CH:17]=2)[N:11]1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.O>C(#N)C>[OH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@@H:10]1[NH:11][C@H:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:33])=[CH:20][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CN(CCc1ccccn1)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(CCc1ccccn1)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1
Reaction time: 1 h
Yield: 26 %

Procedure:
The crude tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-{methyl[2-(pyridine-2-yl)ethyl]carbamoyl}benzyl)pyrrolidine-1-carboxylate was dissolved in a 3:3:1 mixture of acetonitrile (1.4 mL):TFA (1.4 mL):water (0.47 mL), and the mixture was heated to 55° C. and stirred for 1 hour. The mixture was then concentrated in vacuo and purified by mass directed reverse phase HPLC using acetonitrile/water with 0.1% NH4OH buffer. Lyophilization of the desired fractions gave the title compound (21 mg, 26% yield over three steps) as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH:11]=[CH:10]2
Reactant: C1CNCCN1
Reactant: COc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 110 °C
Yield: 50.9 %

Procedure:
To a solution of 2-chloro-6-methoxy-quinoline of Step C, (2.5 g, 12.91 mmol) in N,N-dimethylformamide (50 mL) is added piperazine (12 g) and the mixture is heated at 110° C. under nitrogen for 6 hours. The solution is diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (4–10%) in dichloromethane containing 0.2% ammonium hydroxide to provide the title compound (1.6 g) as an off-white solid, m.p. 95–97° C.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][CH3:21]>>[CH2:19]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][CH3:21]
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CC[K]
Reactant: CCCNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: CCCN(C(=O)C1OC1C(=O)OCC)c1ccccc1
Yield: 56.3 %

Procedure:
Following the procedure of Example 34, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and N-propylaniline (1.4 g) to give 0.78 g of ethyl N-propyl-N-phenyl-2,3-epoxysuccinamate (Compound No. 59) as colorless oil.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=O)[CH:2]=1.C(OP([CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24])(OCC)=O)C>>[C:23]([C:22]1[CH:21]=[C:20]([CH:19]=[CH:9][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=2)[CH:27]=[CH:26][CH:25]=1)#[N:24].[C:23]([C:22]1[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=1)[CH:19]=[CH:9][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:19][C:20]2[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[CH:21]=2)=[CH:1][CH:2]=1)#[N:24]
Reactant: CCOP(=O)(Cc1cccc(C#N)c1)OCC
Reactant: O=Cc1ccc(C=O)cc1
Product: N#Cc1cccc(C=Cc2ccc(C=Cc3cccc(C#N)c3)cc2)c1
Product: N#Cc1cccc(C=Cc2ccc(C=O)cc2)c1
Reaction time: 0.5 h
Yield: 2 %

Procedure:
6.7 g of terephthaldehyde are reacted with 12.8 g of m-diethylphosphonomethylbenzonitrile (99.2%) in accordance with Example 1. The reaction temperature is kept initially at 0°-5° C. for 1/2 hour and allowed to rise overnight to 22° C. 3-Cyanostilbene-4'-aldehyde containing 2% of 1,4-di(m-cyanostyryl)benzene is obtained in a yield of 8.0 g after working up as described in Example 1, but without dilution with water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:15]2)[CH:6]=[C:7]([N+:11]([O-])=O)[C:8]=1[O:9][CH3:10].[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:15]2)[CH:6]=[C:7]([NH2:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(N)c1OC

Procedure:
trans-2-(3,4-Dimethoxy-5-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene (0.3 g, 0.69 mmole) was suspended in 10 ml of ethanol. To this was added CaCl2 (72.63 mg, 0.65 mmole) in 2 mL water, followed by zinc metal (1.01 g). The suspension was refluxed for 5 hours, filtered, and the residue was washed with ethanol. The combined filtrate was washed with 10% NaHCO3, water and saturated aqueous sodium chloride, dried over MgSO4 and evaporated in vacuo to an oil that was purified by flash column chromatography using 1:1 hexane/ethyl acetate as solvent (30 mg, 10.8%). 1H NMR (CDCl3): 2.10 (m, 2H); 2.57 (m, 2H); 3.81 (s, 3H); 3.83 (s, 3H); 3.87 (s, 3H); 3.89 (s, 6H); 4.80 (m, 2H); 6.45 (d, 1H); 6.51 (d, 1H); 6.70 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([NH:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][CH3:15])=[O:13])[CH:7]=1>CO.[Pd]>[NH2:22][C:17]1[CH:16]=[C:4]([C:3]([O:2][CH3:1])=[CH:19][C:18]=1[NH:20][CH3:21])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][CH3:15])=[O:13])[CH:7]=1
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(Oc2cc(N)c(NC)cc2OC)ccn1

Procedure:
A solution of {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. In methanol was hydrogenated with 10% Pd/C. The catalyst was filtered off and the solvent was concentrated to yield {4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS :MH+: 302.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1cccc(OCCCCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methyl 3-(3-chloro-propoxy)-phenylacetate (12.7 g, 52.3 mmol) was dissolved in dioxane (25 mL) and 1N NaOH (53 mL) was added. The mixture was stirred at room temperature for 45 minutes then acidified by addition of 1N hydrochloric acid (60 mL). A white precipitate formed which was filtered, washed with 1N HCl, water and dried. 3-(3-Chloro-propoxy)-phenylacetic acid (11.7 g, 98%). 1H NMR (500 MHz, CDCl3) δ 7.25 (1H, dd), 6.93-6.85 (3H, m), 4.11 (2H, t), 3.79 (2H, t), 3.70 (2H, s), 2.25 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>CC1CCCO1.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCC(=O)O
Solvent: CC1CCCO1
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 98 °C
Yield: 50.4 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 8 ml of 2-methyltetrahydrofuran and 5 ml of propionic acid is heated to its boiling point and maintained at this temperature (98° C.) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with 2-methyltetrahydrofuran. After drying, 0.55 g of raw deferasirox is obtained, i.e. 50% of the theory, with an HPLC purity of 95.3% and a melting temperature of 255 to 262° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]1.[C:21]1([N:27]2[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]3[O:40][N:39]=[C:38]4[C:41]5[C:46]([CH2:47][CH2:48][C:37]=34)=[CH:45][C:44]([CH:49]=[O:50])=[CH:43][CH:42]=5)[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[OH:50][CH:49]([C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[C:38]1=[N:39][O:40][C:36]([C:30]3[CH:29]=[N:28][N:27]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:31]=3[C:32]([F:35])([F:34])[F:33])=[C:37]1[CH2:48][CH2:47]2)[C:14]1[O:13][CH:17]=[CH:16][C:15]=1[C:18]([OH:20])=[O:19]
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: O=C(O)c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ccoc1C(O)c1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 108.2 %

Procedure:
To a stirred solution of diisopropylamine (0.072 mL, 0.508 mmol) in anhydrous THF (0.5 mL) was added a 2.5 M THF solution of n-BuLi (0.203 mL, 0.508 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at the same temperature for 15 min. before being cooled to −78° C. A solution of furan-3-carboxylic acid (28.5 mg, 0.254 mmol) in anhydrous THF (1 mL) was added. The reaction mixture was stirred at −78° C. for 30 min. before a solution of 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 89B, 80 mg, 0.195 mmol) in anhydrous THF (1 mL) was added at the same temperature. The mixture was then allowed to warm to room temperature over 30 min. The reaction was quenched with water (3 mL). The mixture was concentrated and the aqueous residue was acidified with 10% aqueous citric acid solution to pH=3. The mixture was extracted with ethyl acetate (2×3 mL). The combined organic solutions were dried (sodium sulfate) and concentrated to give 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid (110 mg, 0.211 mmol, 108% yield) as green foam solid. Next, 48 mg of the solid was purified by reverse phase preparative HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) to give 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid, TFA (32 mg) as white solid. The compound had an HPLC retention time=3.42 min. (condition C); LC/MS M+1=522.2; 1H NMR (400 MHz, MeOD) δ ppm 8.14 (1H, s), 7.88 (1H, d, J=7.9 Hz), 7.54-7.63 (6H, m), 7.48-7.52 (2H, m), 7.47 (1H, d, J=7.9 Hz), 6.72 (1H, d, J=2.0 Hz), 6.56 (1H, s), 3.03 (2H, t, J=6.9 Hz), 2.89 (2H, t, J=6.9 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:32])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cc(F)cc(Cl)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 87 (0.4 g, 0.71 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.32 g, 2.1 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white solid (Yield, 0.15 g, 36%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:10]=1[CH2:11][C@@H:12]([C:23]([OH:25])=[O:24])[N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(#N)C>[CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:10]=1[CH2:11][C@@H:12]([C:23]([O:25][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:24])[N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC#N
Product: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 7A from 420 mg (0.68 mmol) of the compound from Example 70A, 9.77 mg (0.08 mmol) of DMAP, 173 mg (1.6 mmol) of benzyl alcohol and 184 mg (0.96 mmol) of EDC in 8 ml of acetonitrile.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)C(C)(C)C1C)([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=[O:25])C(C)C.C1(C)C=CC=CC=1>[N+](C)([O-])=O>[CH:1]([C:4]([C:12]1[CH:7]=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=1)=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C(C)C)cc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To prepare 1-isopropyl-2,3,3,5-tetramethylindane, the procedures of Traas et al., U.S. Pat. No. 4,352,748 are substantially followed. Specifically, a solution of aluminum chloride (75 g) in nitromethane (50 ml) is added to a mixture of isobutyroyl chloride (49 g), nitromethane (50 ml) and toluene (100 ml), and stirred for one hour at about 10° C. The reaction mixture is poured over ice and extracted with ether. The ether solution is washed to neutrality, dried and evaporated. The residue is distilled under diminished pressure to obtain p-tolyl isopropyl ketone. The ketone (11 g) is then dissolved in methanol (50 ml), added to a solution of NaBH4 (10 g) in a methanol/water mixture (100 ml; 1:1). The reaction mixture is stirred for one hour, and then poured into water and extracted with ether. The solution in ether is dried on anhydrous magnesium sulfate and evaporated to yield 2-methyl-1-(p-tolyl)propanol-1.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2].[C-]#[C-].[Li+].[Li+].[CH2:28](N)[CH2:29]N>CC(N(C)C)=O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:28]#[CH:29])[OH:23])[CH3:2]
Reactant: NCCN
Reactant: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CCC2=O
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC(C)C4=C(CC=C(OC)C4)[C@H]3CC[C@@]21CC
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
Dissolve dl-13-ethyl-6-methyl-3-methoxygona-2,5(10)-dien-17-one (3.6 g) in dimethylacetamide (35 ml) and stir in a stream of acteylene for 0.5 hour. Add solid lithium acetylide-ethylenediamine (2.7 g) and stir the solution for 4 hours. Pour the reaction mixture onto ice, extract with ether, wash the ether layer with water, dry, and evaporate to obtain dl-13-ethyl-3-methoxy-6-methyl-17α-ethynyl-17-hydroxygona-2,5(10)-diene (3.5 g) as a gum; infrared absorption peaks (sodium chloride) at 2.90 μ, 3.05 μ, 5.90 μ, 6.03 μ.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7](Cl)[N:6]=1)[CH3:2].[Na+].[I-:15].C(Cl)(=O)C>CC#N.CCOC(C)=O>[Cl:11][C:10]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[N:6][C:7]([I:15])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1nc(Cl)ccc1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(=O)Cl
Product: CCOC(=O)c1nc(I)ccc1Cl
Temperature: 100 °C
Yield: 26.8 %

Procedure:
To a solution of 3,6-dichloropicolinic acid ethyl ester (5.0 g, 24 mmol) in CH3CN (45 mL) was added NaI (10 g, 66.7 mmol) and acetyl chloride (2.5 mL). The reaction mass was heated in a sealed tube at 100° C. for 48 h. The reaction mass was diluted with EtOAc and was washed with saturated solutions of Na2S2O3 and NaHCO3. The organic layer was separated, dried, filtered and concentrated to afford 2 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.04 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 4.38 (q, J=7.5 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.ClS([N:21]=[C:22]=O)(=O)=O.CN(C=O)C>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:21])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc(-c3cccnc3)[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1c(-c2cccnc2)[nH]c2cc(F)ccc12
Reaction time: 8 h

Procedure:
To a solution of 6-fluoro-2-pyridin-3-yl-1H-indole (Example 89, 212 mg, 1.0 mmol) in dichloromethane (90 mL) at ambient temperature is added chlorosulfonyl isocyanate (0.71 g, 5 mmol) and the mixture is stirred overnight. Anhydrous DMF (1 mL) is added. After 1 h, the solvent is removed in vacuo and the residue purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to give 6-fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.12-7.21 (m, 1H), 7.39 (dd, J=9.5, 2.4 Hz, 1H), 7.64-7.74 (m, 2H), 8.27-8.35 (m, 1H), 8.73 (dd, J=4.9, 1.6 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 12.89 (s, 1H). MS (ESI) m/z 238.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])=[O:4].Br[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[O:21][N:20]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[S:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[O:21][N:20]=2)[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1[nH]c(-c2ccccc2)nc1C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C)nc(-c2ccccc2)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 60 mg 5-Methyl-2-phenyl-3H-imidazole-4-carboxylic acid methyl ester in 1 ml DMF 95 mg caesium carbonate and 82 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and the mixture was stirred for 2 h at 60° C. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 78 mg.