Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:10])[CH2:3][N:4]([CH2:6][CH:7](O)[CH3:8])[CH3:5].C(P(CCCC)CCCC)CCC>[Ru](Cl)(Cl)Cl.COCCOCCOCCOCCOC>[CH3:8][CH:7]1[O:10][CH:2]([CH3:1])[CH2:3][N:4]([CH3:5])[CH2:6]1
Reactant: CC(O)CN(C)CC(C)O
Agent: Cl[Ru](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Agent: COCCOCCOCCOCCOC
Product: CC1CN(C)CC(C)O1
Temperature: 180 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A 300 ml stirred autoclave with pyrex liner was charged a mixture of N-methyldiisopropanolamine (60 g, 0.41 mol), tributylphosphine (1.6 ml), ruthenium trichloride (0.520 g) and tetraglyme (30 ml). The reactor was sealed and purged of air. The reaction was heated to 180° C. and held for three hours. The reaction was allowed to cool to room temperature. The reaction mixtures were distilled to obtain a 90% yield of 2,4,6-trimethylmorpholine.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:17][CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:28][C:23]=2[N:22]=[CH:21]1>>[CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:28][C:23]=3[N:22]=[CH:21]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc(OCC2CO2)cc1
Reactant: NCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Product: CS(=O)(=O)Oc1ccc(OCC(O)CNCCn2cnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-(4-methylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=C.[CH3:13][C:14]1C2C(=CC=CC=2)C=CC=1C=C.CC1(C=C)C=CC2C(=CC=CC=2)C1.CC1C2C(=CC=CC=2)C=C(C=C)C=1.COC1C2C(=CC=CC=2)C=C(C=C)C=1>>[CH:13]([C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[CH:3][CH:4]=2)[CH:9]=[CH:8][CH:7]=1)=[CH2:14]
Reactant: C=Cc1ccc2ccccc2c1
Reactant: C=Cc1ccc2ccccc2c1C
Agent: C=CC1(C)C=Cc2ccccc2C1
Agent: C=Cc1cc(C)c2ccccc2c1
Agent: C=Cc1cc(OC)c2ccccc2c1
Product: C=Cc1cccc2ccccc12

Procedure:
2-vinylnaphthalene, α-methyl-2-vinylnaphthalene, β-methyl-2-vinylnaphthalene, 4-methyl-2-vinylnaphthalene, 4-methoxy-2-vinylnaphthalene, etc.;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][Mg]Cl)=[CH:21][CH:20]=1>CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:23][C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(C[Mg]Cl)cc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(O)(Cc2ccc(F)cc2)CC1
Temperature: -40 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
To a round bottom flask equipped with a magnetic stirring bar was added 2.94 g of 4-oxo-piperidine-1-carboxylic acid benzyl ester (12.6 mmol, 1.0 equiv) and 25 mL of ether. The flask was fitted with a septum and a nitrogen inlet and cooled to −40° C. A 0.25 M solution of (4-fluoro)benzylmagnesium chloride (50 mL, 12.5 mmol, 1.0 equiv.) was added via syringe over 10 minutes to the reaction solution. After 1 h, the mixture was warmed to room temperature and stirred for 20 h. Then the solution was cooled to 0° C. and quenched with 30 mL of saturated aqueous ammonium-chloride. The aqueous layer was extracted with 100 mL of EtOAc. The combined organic layers were washed with saturated aqueous NaCl (3×25) and dried over MgSO4. The resultant yellow oil was purified by flash chromatography to afford 1.058 g of 4-(4-Fluoro-benzyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (3.08 mmol, 25% yield). The crude product was diluted in methanol (12 mL) and added to a round bottom flask containing a magnetic stirring bar and 200 mg of 10% Pd/C. The flask was evacuated, and back-filled with hydrogen (1 atm). After 24 h of vigorous stirring under nitrogen atmosphere, the solution was filtered through celite and concentrated in vacuo to afford 4-(4-fluoro-benzyl)-piperidin-4-ol (67) in quantitative yield (644 mg): HPLC retention time=0.26 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected=210.1, found 210.1.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.Cl.[Cl-].[CH2:46]([N:48]1[CH:52]=[C:51]([CH2:53][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:50]=[CH:49]1)[CH3:47].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:46]([N:48]1[CH:52]=[C:51](/[CH:53]=[CH:1]/[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:33]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[N:50]=[CH:49]1)[CH3:47]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Reactant: CCn1cnc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4cn(CC)cn4)cc3OC)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (3.00 g), [(1-ethyl-1H-imidazol-4-yl)methyl](triphenyl)phosphonium chloride hydrochloride (3.43 g), anhydrous potassium carbonate (1.07 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hrs. To the reaction mixture were added [(1-ethyl-1H-imidazol-4-yl)methyl](triphenyl)phosphonium chloride hydrochloride (1.14 g) and anhydrous potassium carbonate (356 mg) and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (9:1 to 1:0, v/v) to give ethyl (4-{4-[(4-[({4-[(E)-2-(1-ethyl-1H-imidazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals (352 mg, yield 10%). melting point: 140-141° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(F)ccc1COc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(F)ccc1COc1cccc(F)c1
Yield: 88.5 %

Procedure:
To a solution of 15 g of ethyl 5-fluoro-2-[(3-fluorophenyloxy)methyl]benzoate in 200 ml of ethanol is added 100 ml of 5% aqueous sodium hydroxide and the mixture is refluxed with heating for 1 hour. After cooling, the solvent is distilled off under reduced pressure and the residue is added with 300 ml of water and then with 10% hydrochloric acid to make the mixture acidic. The precipitated crystals are collected by filtration and dried to give 12 g of 5-fluoro-[(3-fluorophenyloxy)methyl]benzoic acid. Mass spectrum m/z: 264(M+).
Reaction SMILES: C(OC1C=CC=CC=1[C@H](C)C([N:18]1[CH2:26][C@@H:25]2[C@@H:20]([CH2:21][C@@H:22]([CH3:36])[CH2:23][C@:24]2(C2C=CC=CC=2OC)[OH:27])[CH2:19]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:36][CH:22]1[CH2:21][CH:20]2[CH:25]([CH2:26][NH:18][CH2:19]2)[CH:24]([OH:27])[CH2:23]1
Reactant: COc1ccccc1[C@]1(O)C[C@H](C)C[C@H]2CN(C(=O)[C@@H](C)c3ccccc3OCc3ccccc3)C[C@H]21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CC(O)C2CNCC2C1

Procedure:
To a solution of 0.85 g of (3aS,4S, 6R, 7aR)-2-[2-(S)-(2-benzoxyphenyl) propionyl]-4-(2-methoxyphenyl)-6-methyl-4-perhydroisoindolol in 12 cm3 of absolute ethanol is added 0.2 g of 20% palladium hydroxide on charcoal, and hydrogen is sparged through the reaction mixture at 40° C. for 3 hours. After returning to room temperature and flushing with argon, the mixture is filtered over fire and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in ethanol and, after filtration and drying, 0.5 g of (3aS,4S,6R,7aR)-2-(S)-(2-hydroxyphenyl) propionyl]-4-(2-methoxtphenyl)-6-methyl-4-perhydroisoindolol is obtained, in the form of white crystals melting at 280° C.; [α]D =-26.5° (c=5.3 g/l , CHCl3).
Reaction SMILES: [C:1]1([CH3:30])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]2[C:11](=[O:29])[N:12]([CH2:18][C:19]([O:21]CC3C=CC=CC=3)=[O:20])[C:13]([CH3:17])=[C:14](Cl)[N:15]=2)=[CH:3][CH:2]=1.[OH-].[K+].O>[Pd].O1CCCC1.CO>[C:1]1([CH3:30])[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:9][C:10]2[C:11](=[O:29])[N:12]([CH2:18][C:19]([OH:21])=[O:20])[C:13]([CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)cc1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CCNc2ncc(C)n(CC(=O)O)c2=O)cc1
Reaction time: 72 h
Yield: 22.7 %

Procedure:
A mixture of 3-(2-4-tolylethylamino)-5-chloro-6-methyl-1-(benzyloxycarbonylmethyl)pyrazinone (854 mg, 2.00 mmol), as prepared in the preceding step, potassium hydroxide (452 mg, 8.00 mmol), 10% palladium on carbon (254 mg) in tetrahydrofuran (20 mL), methanol (30 mL), and water (7 mL) was stirred under hydrogen balloon for three days. The mixture was filtered through Celite. The filtrate was adjusted to pH 2–4 with 10% HCl and concentrated to about 2 mL under reduced pressure. The white solid which precipitated from the solution was filtered, washed with a small amount of water, and dried to give the title compound (137 mg, 22.7%). 1H NMR (CDCl3) δ 7.20 (d, 2 H, J=7.5 Hz), 7.10 (d, 2 H, J=7.8 Hz), 6.70 (s, 1 H), 4.71 (s, 2 H), 2.87 (m, 2 H), 2.50 (m, 2 H), 2.26 (s, 3 H), 2.15 (s, 3 H).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][O:11][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 96.3 %

Procedure:
8,9 and 10 To a stirred mixture of Boc-prolinol (3.00 g, 14.9 mmol), ethyl p-hydroxybenzoate (2.40 g, 14.5 mmol), and triphenylphosphine (3.91 g, 14.9 mol) in THF (80 mL) was added dropwise diethyl azodicarboxylate (2.86 g, 16.4 mmol) at room temp. After the addition was completed, the resulting mixture was heated under reflux for 2 hr. After cooling, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed successively with 1 N NaOH, water, brine. The EtOAc layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:4, v/v) as eluent to give 4.88 g (93%) ethyl (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoate as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]3=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[N:35]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[NH:33][N:32]=4)[CH2:27][CH2:26]3)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>CC(C)=O>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]3=[N:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[NH:35][C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)=[N:33][N:32]=4)[CH2:29][CH2:30]3)=[CH:22][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccn2c(-c3ccccc3)c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)nc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Product: N#Cc1ccn2c(-c3ccccc3)c(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 3.0 g 3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyridine-7-carbonitrile (prepared as described under example 29) in 50 ml acetone is added a solution of 0.714 g fumaric acid in. The reaction mixture is stirred at ambient temperature for 3 d. The desired compound is collected by filtration and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O>COCCOC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:13]=[C:11]([CH2:10][Cl:9])[N:1]=2)[CH:4]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccc(Br)cn1
Solvent: COCCOC
Product: ClCc1cn2cc(Br)ccc2n1
Yield: 10.4 %

Procedure:
A mixture of 2-amino-5-bromopyridine (10.0 g). 1,3-dichloroacetone (7.71 g) and 1,2-dimethoxyethane (40 ml) was stirred at room temperature for 4 hours. The precipitated crystals were collected by filtration, to which ethanol (100 ml) was added and heated under reflux. The reaction mixture was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give crystals of 6-bromo-2-chloromethylimidazo-[1,2-a]pyridine (1.48 g, 10%). Recrystallization from ethyl acetate-hexane gave colorless needles, mp 129-130° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[CH:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[CH:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: N#CCCC=C1CCCN(Cc2ccccc2)C1
Agent: [Ni]
Solvent: CCO
Product: NCCCC=C1CCCN(Cc2ccccc2)C1

Procedure:
8.0 g (33.3 mmol) 4-(1-benzylpiperidin-3-ylidene)-butyronitrile are dissolved in 80 ml ethanol and added to a spatula tip of Raney-Nickel. The mixture is stirred under hydrogen atmosphere until consumption of the theoretical amount of hydrogen to be taken up (ca. 5 days). The mixture is filtered from the catalyst and the solvent is removed under vacuum. The residue is chromatographically purified Voice over silica gel with CHCl3/CH3OH/NH4OH (90/10/1). After drawing off the solvent, a colorless oil remains which is further processed without additional purification. Yield. 3.9 g (47%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]2[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]=2[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5](C)[CH:4]=1)#[N:2].[Cl:37]C1C=C(C=CC=1C=O)C#N>>[Cl:37][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[N:9]([CH2:17][C:18]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1ccc(C=O)c(Cl)c1
Reactant: Cc1cc(C#N)ccc1N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1Cl

Procedure:
The title compound is prepared in analogy to tert-butyl (4-cyano-2-methylphenyl)(6-oxo-2-(3-(trifluoromethyl)phenylamino)cyclohex-1-enyl)methylcarbamate (intermediate 51), using 3-chloro-4-formylbenzonitrile (500 mg, 6.04 mmol) as starting material. Yield: 1.05 g; ESI mass spectrum [M+H]+=520; Retention time HPLC: 0.81 min (X012_S01).
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([NH:5][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: COc1c(N)cccc1F
Agent: Br
Product: COc1c(F)cccc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 60.7 %

Procedure:
3-fluoro-2-methoxyaniline (115 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-fluoro-2-methoxyphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (57 mg, 60%) as a white solid. Mass Spectrum: M+H+ 470. NMR Spectrum (DMSOd6): 1.59 (d, 3H), 2.70 (bs, 3H), 2.93 (bs, 3H), 3.50-3.63 (m, 4H), 3.71-3.79 (m, 4H), 3.83 (s, 3H), 5.02-5.11 (m, 1H), 5.60 (s, 1H), 5.95 (d, 1H), 6.11 (d, 1H), 6.39 (dd, 1H), 6.72 (ddd, 1H), 7.59 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:36][CH:37]([CH3:39])[CH3:38])=[C:32]([CH:35]=1)[C:33]#[N:34]>CN(C=O)C>[C:33]([C:32]1[CH:35]=[C:28]([CH:29]=[CH:30][C:31]=1[O:36][CH:37]([CH3:39])[CH3:38])[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:34]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(OC(C)C)c(C#N)c3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (1.237 g, 4.77 mmol) was dissolved in DMF (12 mL) and cesium carbonate (1.554 g, 4.77 mmol) was added. The reaction mixture was stirred at room temperature for 10 min and 5-(chloromethyl)-2-isopropoxybenzonitrile (1.0 g, 4.77 mmol) was added. The reaction mixture was stirred at 40° C. for 2 h before it was cooled to room temperature. The heterogenous mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.32 g). LCMS m/z=433.5 [M+H]+; NMR. (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 1.40 (d, J=6.1 Hz, 6H), 2.05-2.16 (m, 1H), 2.50 (dd, J=16.7, 11.1 Hz, 1H), 2.69-2.88 (m, 4H), 3.50-3.59 (m, 1H), 4.16-4.26 (m, 2H), 4.65 (septet, J=6.1 Hz, 1H), 5.00 (s, 2H), 6.80 (dd, J=8.7, 2.5 Hz, 1H), 6.94-6.97 (m, 2H), 7.20 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.7, 2.3 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 8.45 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CO.C(=O)(O)[O-].[Na+]>ClCCl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(I)cc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)S(=O)N=Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
4-Iodobenzaldehyde (1.26 g, 5.43 mmol) was dissolved in dichloromethane (41.8 mL). 2-methylpropane-2-sulfinamide (0.679 g, 5.43 mmol) was added, followed by titanium(IV) ethoxide (2.25 mL, 10.9 mmol). The reaction was heated to reflux for 1 hour. The reaction was then allowed to cool to room temperature and stir for 18 hours. Methanol (8.0 mL) and saturated sodium bicarbonate (1.5 mL) were added to the reaction mixture. The resulting slurry was filtered through sodium sulfate, and rinsed with ethyl acetate. The filtrate was concentrated to yield the title compound N-(4-iodobenzylidene)-2-methylpropane-2-sulfinamide (1.69 g, 93%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.51 (s, 1H), 7.80-7.84 (m, 2H), 7.53-7.57 (m, 2H), 1.25 (s, 9H). MS (M+1): 336.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[N+:13]([O-])([OH:15])=[O:14]>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C=O)c1OC
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Reaction time: 0.08 h

Procedure:
50.0 g (301 mmol) 2,3-Dimethoxy-benzaldehyd (Aldrich) were slowly added to nitric acid at 0° C. The reaction mixture was stirred for 5 minutes, diluted with water until no further precipitate was obtained. After filtration the residue was washed with methanol.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[C:28]([Cl:35])[CH:27]=1.C(N(CC)CC)C>ClCCCl>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:34])=[C:28]([Cl:35])[CH:27]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: c1ccc(-n2nc3c(c2NC2CCCCC2)CCCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc(NC(=O)N(c2c3c(nn2-c2ccccc2)CCCC3)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-amine (example 45) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of triethylamine for 120 h under reflux conditions to give the title compound as yellow solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: [CH3:1][S:2]([CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:4])=O.Cl[C:21]1[CH:26]=CC=C(C(OO)=O)[CH:22]=1>>[CH2:1]([S:2]([CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4])[CH2:22][CH2:21][CH3:26]
Reactant: CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCS(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The procedure for making bis(p-chlorophenyl)methyl methyl sulfone was followed, using a slight excess of m-chloroperbenzoic acid (0.027 mole acid to 0.025 mole of bis(p-chlorophenyl)methyl n-butyl sulfoxide). A light amber liquid was formed and this gave crystals which were recrystallized from methanol as a white solid of bis(p-chlorophenyl) methyl n-butyl sulfoxide, melting point 116°-188° C.