Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@H:19]([CH3:22])[CH:20]=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1CN2C(=NCCC2)C1.[BH4-].[Na+].CCCCCC.C(OC(=O)C)C>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O)(C)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@@H:19]([CH3:22])[CH2:20][OH:21])([CH3:6])([CH3:7])[CH3:5]
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: C1CN=C2CCCN2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Yield: 50.7 %

Procedure:
1740 mg of (S)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethylsilanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-al was dissolved in anhydrous THF (35 ml). DBN (640 ml; 5,36 mmol) was added and the mixture was refluxed for four hours. The reaction mixture, after cooling, was poured in cold citric acid solution, extracted with ethyl-acetate, washed with brine and dried over Na2 SO4. Removal of the solvent afforded a crude colourless oil (approximately 1:1 mixture at C(20)). The crude mixture was then dissolved in isopropanol (40 ml), cooled to 0° C., and NaBH4 (232 mg; 6,13 mmol) was added. The cooling bath was removed and stirring was continued for half an hour at room temperature. The reaction mixture was poured in cold brine, extracted with ethyl-acetate, dried over Na2 SO4. Removal of the solvent afforded a colourless oil. HPLC chromatography (eluent: n-hexane/ethyl-acetate 85:15) allowed the separation of both diastereoisomers affording 887 mg (50,7%) of the desired (R)-2-[(1R,3aR,4S,7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-ol as a colourless oil.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[CH3:21].C(N(CC)C(C)C)(C)C.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>C(Cl)Cl>[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=2)=[O:39])=[CH:16][C:15]=1[CH3:21]
Reactant: Cc1cc(N)ccc1N1CCc2ccncc2C1
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)c(C)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-3-methylaniline trihydrochloride (24.7 mg, 0.071 mmol) and N,N-diisopropylethylamine (0.043 mL, 0.25 mmol) in 1.0 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.013 mL, 0.106 mmol) and the reaction stirred at rt for 1.5 hours. The reaction was quenched into a brine/aqueous Na2CO3 solution, then extracted with EtOAc. The EtOAc layer was washed with brine/aqueous Na2CO3 solution, dried with anhydrous Na2SO4, and evaporated to an oily solid. The oil was chromatographed eluting with CHCl3/EtOAc plus 0.5% MeOH to give the title compound as a faint yellow solid (26 mg, 97%). 1H NMR (Acetone-d6) δ: 8.35 (s, 1H), 8.32 (d, J=5.0 Hz, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.29-7.40 (m, 4H), 7.08-7.17 (m, 3H), 6.80 (d, J=7.3 Hz, 1H), 4.07 (s, 2H), 3.15-3.20 (m, 2H), 2.97-3.03 (m, 2H), 2.30 (s, 3H), 2.29 (s, 3H)
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH2:4][CH2:3][C:2]1=[O:11]>[Pt](=O)=O>[NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCC2=C(CCCC2)N1
Agent: O=[Pt]=O
Product: O=C1CC[C@@H]2CCCC[C@@H]2N1
Yield: 43.2 %

Procedure:
One gram of platinum(IV) oxide was added to a solution of 80 g of 3,4,5,6,7,8-hexahydro-1H-quinolin-2-one and this was hydrogenated at 20° to 25° C. under normal pressure. After filtration of the reaction solution, it was evaporated and the residue was fractionally crystallized from n-hexane. 35 g of cis-octahydro-1H-quinolin-2-one having a melting point of 123° to 126° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:13]([OH:26])[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[O:27]1[CH:31]=[CH:30][CH2:29][CH2:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1([N:13]([O:26][CH:28]2[CH2:29][CH2:30][CH2:31][O:27]2)[C:14](=[O:25])[CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: C1=COCC1
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(N(OC2CCCO2)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1

Procedure:
To a solution of 4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.3 obtained in analogy to preparation example 11, step 4) (70 g, 192.1 mmol) in dichloromethane (1500 ml) under argon atmosphere was added 2,3-dihydro-furan (29.1 ml, 26.9 g, 384.1 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (1.94 g, 19.2 mmol). The reaction mixture was stirred at reflux for 7 hours, filtered and concentrated. The residue was triturated with hexane, filtered and the solid dried in vacuo. Yield: 70.0 g of 1-methoxy-4-{(tetrahydro-furan-2-yloxy)-[2-(2,4,6-trimethyl-phenyl)acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (compound P3ii.6) as a solid, mp 107-109° C. This material was used without further purification in the next step.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[OH:18][C:19]1C=CC(C#N)=CC=1OC>>[CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]#[N:15])=[CH:11][C:10]=2[O:18][CH3:19])=[CH:5][CH:4]=1)=[O:2]
Reactant: COc1cc(C#N)ccc1O
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)s2)cc1
Product: COc1cc(C#N)ccc1Oc1ccc(C=O)s1
Yield: 17 %

Procedure:
Using a method similar to preparation of the compound of Example 1 part A, method A, and using 4-hydroxy-3-methoxy-benzonitrile (859 mg, 5.76 mmol) gives the title compound (225 mg, 17%). 1H NMR (Cl3CD): 9.71 (s, 1H), 7.54 (d, J=4.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.53 (d, J=4.2 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9](OC)=[O:10])=[CH:5][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:5][N:6]=1
Reactant: COC(=O)CCc1cnc(C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(CCCO)s1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A solution of 10.9 g of methyl 2-methyl-5-thiazolepropanoate in 70 ml of tetrahydrofuran was slowly added with stirring at 10° to 15° C. to a mixture of 3.42 g of lithium aluminum hydride in 125 ml of tetrahydrofuran and the mixture was stirred for about 30 minutes. Tetrahydrofuran containing 20% of water was slowly added to the mixture which was then filtered. The residue was washed with ethyl acetate; the filtrate was dried over magnesium sulfate and evaporated to dryness to obtain 8.4 g of raw product which was rectified under reduced pressure to obtain 6.4 g of 2-methyl-5-thiazole-propanol with a boiling point of 106° C. at 0.05 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].N1CCCCC1>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:18]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-Cyanobenzaldehyde (3.00 g, 22.9 mmol) ad ethyl cyanoacetate (2.59 g, 22.9 mmol) are dissolved in absolute ethanol (100 ml). Piperidine (0.097 g, 1.14 mmol) is added, and the solution is stirred at room temperature until no more starting material is apparent by tic. This takes approx. 2 hours during which time a precipitate is formed. The precipitate is filtered and recrystallised, or alternatively, the crude reaction mixture is concentrated in vacuo and chromatographed over silica with cyclohexane/ethyl acetate mixtures as eluent to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>CN(C=O)C.O>[O:30]=[C:29]1[NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=2[CH2:4][CH2:5][N:6]1[CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(2-aminophenethylamino)piperidine-1-carboxylate (6.9 g, 30 mmol) in DMF (110 ml) was added CDI (4.86 g, 30 mmol) in portions followed by stirring the reaction mixture at RT for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organics were combined, washed with water, brine, and evaporated to dryness to give the desired product. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=346; tR=3.24.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[C:8]=2[CH3:13])[N:3]=1.Br[C:18]1[C:23]2[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(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>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]4[C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[O:26][C:22]=4[CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH3:13])[N:3]=1
Reactant: Cc1c(B(O)O)ccc2nc(N)nc(N)c12
Reactant: CC1(C)Oc2cccc(Br)c2C1=O
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: CN(C)C=O
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)ccc2nc(N)nc(N)c12
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A solution of 2.1 grams (0.010 mole) of (2,4-diamino-5-methylquinazolin-6-yl)boronic acid in 25 mL of N,N-dimethylformamide is stirred, and 2.1 grams (0.009 mole) of 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone (prepared in Step C of this Example), 2.8 grams (0.020 mole) of potassium carbonate, and 0.31 gram (catalyst-3 mole %) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction mixture is then warmed to 90° C., where it is stirred for about 16 hours. After this time the reaction mixture is poured into water. The resultant precipitate is collected by filtration and dried, yielding 2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)quinazoline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[C:17]([O-])(=[O:19])[CH3:18].[Na+].O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11]([O:16][C:17](=[O:19])[CH3:18])=[CH:12][C:13](=[O:15])[CH2:14]1
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2Br)C1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC1=CC(=O)CC(c2ccc(F)cc2Br)C1
Temperature: 100 °C

Procedure:
The title compound was prepared reacting 5-(2-bromo-4-fluoro-phenyl)-cyclohexane-1,3-dione (example 1/f stage 2) (5 g, 17.4 mmol) and sodium acetate (1.42 g, 17.4 mmol) in neat acetic anhydride (30 ml). The reaction mixture was heated for 2 h at 100° C. and allowed to cool to ambient temperature whereupon water (60 ml) was added. The mixture was extracted with EtOAc (2×80 ml) and the combined organic layers washed with sat aq sodium bicarbonate until the pH was neutral. Then the organics were dried over sodium sulphate, filtered, and the solvent removed in vacuo.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([C@H]1CC[C@H](OC2C=CC3C(=CC=C(C([N+]([O-])=O)C)C=3)C=2[C:59]([F:62])([F:61])[F:60])CC1)(C)(C)C>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([C:59]([F:62])([F:61])[F:60])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Reactant: CC(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Product: COC(=O)CCC(C)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
Methyl 4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-nitropentanoate was synthesized as per methyl 4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-nitropentanoate (Example 205) in 62% yield using 2-(trans-4-tert-butylcyclohexyloxy)-6-(1-nitroethyl)-1-(trifluoromethyl)naphthalene as starting material.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)#[N:2].[NH2:27][NH2:28].O>CO>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([C:1]([NH:27][NH2:28])=[NH:2])[N:4]=[C:5]2[O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(F)cc23)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(F)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (400 mg, 1.12 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL). The reaction mixture was heated to reflux for 2 hours. The solvent was subsequently removed to give the title compound as a white solid, which was used in next step without purification (450 mg, 100%). ESI-MS m/z [M+H]+ 390.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=1.[OH-].[K+]>CO>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([SH:4])[CH:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: COc1cc(C)cc(SC(=O)N(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)cc(S)c1
Yield: 99.8 %

Procedure:
A mixture of S-3-methoxy-5-methylphenyl dimethylcarbamothioate (10) (4.10 g, 18.2 mmol) and KOH (6.0 g) in MeOH (200 mL) was refluxed for 2 h. After cooling, the mixture was concentrated and diluted with EtOAc (500 mL). The organics were washed with 1N HCl (50 mL), brine (2×50 mL), dried (Na2SO4), and concentrated to give 3-methoxy-5-methylbenzenethiol (11) (2.80 g, quant.) as a colourless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5](=[O:12])[NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CS(C)=O>[CH2:20]([O:13][C:3]1[C:2]([NH2:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5](=[O:12])[N:4]=1)[CH3:21]
Reactant: CCOC(=O)C1C(N)C(=O)NS1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1=C(N)C(OCC)=NS1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.55 g (7.6 mmole) of 4-amino-5-ethoxycarbonylisothiazolin-3-one-1-oxide, 1.38 g (10.0 mmole) of potassium carbonate, and 0.64 ml (8.0 mmole) of ethyl iodide in 6 ml dimethylsulfoxide was stirred at room temperature for 18 hours. The suspension was then poured onto crushed ice and extracted with ethyl acetate (3×30 ml). The combined organic phases were washed one time each with ice water and brine, then dried over sodium sulfate. The title compound, which was obtained upon removal of the solvent, was identical to the product of Example 7.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH2:17][CH3:18])[CH2:15][CH3:16]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH2:17][CH3:18])[CH2:15][CH3:16]
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1N
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(CC)CNCCC1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.8 g) and 4-amino-1-benzyl-3,3-diethylpiperidine (8.0 g, 32.52 mmol) in methanol (100 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,3-diethylpiperidine. Yield 4.8 g (94.60%), C9H20N2, m/z 157 (M+1), PMR (CDCl3): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H, D2O exchangeable), 2.26-2.68 (m, 4H), 3.06 (m, 1H), 3.52 (bs, 1H, D2O exchangeable).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:15][C:16]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:2]=2[I:1])=[O:6])[CH2:28][CH2:27]1
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3I)CC2)c(F)c1

Procedure:
Example CM was prepared in analogy to Example 123 from 2-Iodo-5-methanesulfonyl-benzoic acid (example BQ) and 1-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazine (commercial). MS (m/e): 567.0 (M+H+, 100%).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:24])[NH:5][C:6](=[O:23])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].S(OCC)(O[CH2:35][CH3:36])(=O)=O.CN(C)C=O>C(OCC)(=O)C>[CH2:35]([O:1][C:2]1[N:3]=[C:4]([CH3:24])[NH:5][C:6](=[O:23])[C:7]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)[CH3:36]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1nc(O)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
A mixture of 4′-[(4-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (3.01 g), diethyl sulfate (0.41 mL) and N,N-dimethylformamide (20 mL) was stirred at 0° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.17 g, 16%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH2:5]/[C:4](=[CH:8]/[CH2:9]O)/[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2]>[CH:8](=[C:4]1/[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][CH2:6][CH2:5]/1)/[CH3:9]
Reactant: CC1(C)CCC/C(=C/CO)C1
Agent: [Ti+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C/C=C1/CCCC(C)(C)C1
Yield: 84.8 %

Procedure:
A solution of 2.5 g of (Z)-2-(3,3-dimethyl-1-cyclohexylidene)-1-ethanol [see, for example, A. Gutmann et al., J. Chem. Ecology 7, 919 (1981)] in THF (tetrahydrofuran) was added dropwise, under stirring and argon, to a mixture of LiAlH4 (2 g) and titanocene dichloride (Fluka, 4 spatula tips) in absolute THF at -40°. The reaction mixture was left under stirring at room temperature during the weekend. After washing with water (2 ml), 15% NaOH (2 ml) and again water (6 ml) to hydrolyze, and filtering, 1.9 g of (Z)-3-ethylidene-1,1-dimethylcyclohexane were obtained and used as such in the following step. A small quantity of this product was bulb-to-bulb distilled for analysis:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Reactant: CC(C)(O)CN
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (92.5 g, 321 mmol) and dichloromethane (1.5 L) was cooled to 10° C. 1-Amino-2-methylpropan-2-ol (63.01 g, 707 mmol) was added dropwise over a period of 30 minutes; during the addition, the reaction temperature did not rise above 13° C. The reaction mixture was allowed to warm to room temperature slowly and stirred overnight. The solvent was removed under reduced pressure, and the solid residue was mixed with deionized water (200 mL). The solid was isolated by filtration, washed with deionized water (2×200 mL), and dried in a vacuum oven overnight at 35° C. to provide 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6](O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: Oc1nccc2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ncccc12
Temperature: 80 °C
Yield: 87 %

Procedure:
The product from Example 36d (0.250 g, 1.71 mmol) was combined with phosphorous oxychloride (4 mL) and heated under a nitrogen atmosphere at 80° C. for 18.5 h followed by vacuum distillation to remove the volatiles. The residue was slurried with ice and made basic (pH 7-8) with concentrated ammonium hydroxide. The title compound was collected by vacuum filtration, water washed and dried under vacuum to give a gray solid (0.245 g, 87%) sufficiently pure for use as isolated.