Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[CH2:13])[C:11]#[N:12].[OH-].[Na+]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OC)(C)(C)C.O>[C:11]([C:10](=[CH2:13])[CH:9]([O:8][C:1](=[O:3])[CH3:2])[CH:14]([CH3:16])[CH3:15])#[N:12]
Reactant: C=C(C#N)C(O)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=C(C#N)C(OC(C)=O)C(C)C
Temperature: 50 °C
Yield: 95.2 %

Procedure:
To a 500 mL, four-necked, round-bottom flask equipped with an overhead stirrer, a temperature probe, a reflux condenser, and a nitrogen inlet is charged acetic anhydride (40 mL, 0.45 mol). This solution is heated to 50° C. and a solution of 3-hydroxy-4-methyl-2-methylenepentanenitrile (50 g, 0.40 mol) and 4-(dimethylamino)pyridine (1.5 g) in tetrahydrofuran (25 mL) is added over 35 minutes. A temperature of 50° C. to 63° C. is maintained without external heating. After the addition is complete, the reaction mixture is heated at 60° C. for 75 minutes. The solution is cooled to 30° C. and the cooled reaction mixture is diluted with 30 mL of tert-butylmethyl ether (MTBE) and 25 mL of water. This mixture is cooled to 10° C. and a solution of 50% aqueous sodium hydroxide (37 g, 0.46 mol) diluted with 45 mL of water is added with cooling, such that the temperature is maintained at about 15° C. For the final pH adjustment, 50% aqueous sodium hydroxide 9.8 g (0.12 mol) is added dropwise to a final pH of 9.4. After adding 10 mL of water and 10 to 15 mL of MTBE, the reaction mixture is phased and separated. The upper organic product layer is separated and washed with 25 mL of brine, dried over magnesium sulfate, and concentrated in vacuo to provide 63.7 g (95%) of acetic acid 2-cyano-1-isopropyl-allyl ester as a pale yellow oil. Ethyl 3-cyano-5-methyl hex-3-enoate
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Oc2c(Cl)cncc2Cl)s1
Reactant: CC(C)N1CCC(N)CC1
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Oc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-((3,5-dichloropyridin-4-yl)oxy)-4-nitrothiophene-2-carboxylic acid (10 mg, 0.03 mmol) from above and 1-isopropylpiperidin-4-amine (17.4 mg, 0.1 mmol). The title compound was obtained as a solid (1.0 mg, 7% yield). MS m/z: 459.01, 461.01 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]1)=[O:7].C(N(C(C)C)CC)(C)C.[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([CH:45](Br)[C:46]2[CH:51]=[CH:50][C:49]([CH2:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=2)=[CH:41][CH:40]=1)[CH:36]([CH3:38])[CH3:37].Cl>ClCCl>[CH2:52]([C:49]1[CH:50]=[CH:51][C:46]([CH:45]([NH:2][C:3]2[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=2)[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]2)=[O:7])[C:42]2[CH:43]=[CH:44][C:39]([CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:40][CH:41]=2)=[CH:47][CH:48]=1)[CH:53]([CH3:55])[CH3:54]
Reactant: CC(C)Cc1ccc(C(Br)c2ccc(CC(C)C)cc2)cc1
Reactant: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3ccccc32)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)n3cc(CCCC(=O)O)c4ccccc43)c2)c2ccc(CC(C)C)cc2)cc1
Reaction time: 15 h
Yield: 95.5 %

Procedure:
To a solution of 4-[1-(3-aminobenzoyl)indol-3-yl]butyric acid hydrochloride (14.5 g) and diisopropylethylamine (22 ml) in dichloromethane (300 ml) was added bis(4-isobutylphenyl)methyl bromide (14.5 g) at room temperature. After stirring for 15 hours, diisopropylethylamine (7 ml) and bis(4-isobutylphenyl)methyl bromide 2.0 g) were added to the mixture. The mixture was stirred for 6 hours at room temperature and acidified by 7% hydrochloric acid (50 ml). The separated organic layer was washed with water and dried over magnesium sulfate. After the solvent was removed in vacuo, the residue was chromatographed on a column of silica gel (200 g) and eluted with chloroform to give a solid of 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-3-yl]butyric acid (23.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[OH:24].[N:25]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([CH3:22])([CH3:23])[CH2:20][NH:21][C:32](=[O:33])[CH2:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[OH:24]
Reactant: CC(C)(CN)c1cc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)o1
Reactant: O=C(O)CN1CCOCC1
Product: CC(C)(CNC(=O)CN1CCOCC1)c1cc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)o1

Procedure:
The title compound was prepared from the product of Example 7 Step 2 and morpholin-4-yl-acetic acid as described in Example 4 Step 3; MS (ES+) m/e 470, 472 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH:5]=[C:6]([CH3:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1>CC(C)=O>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C:6](=[CH2:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: CC1=C[C@@H]2C[C@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@H]3[C@H]12
Solvent: CC(C)=O
Product: C=C1C[C@@H]2C[C@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@H]3[C@H]12
Yield: 36.7 %

Procedure:
Hydrolysis of fraction 2 (2% acetone), as above, gave: 3α-hydroxy-7-methyl-5β-chol-6-enoic acid (3.0 g, mp, 121°-122° C.). Hydrolysis of fraction 3, (2% acetone), as above, gave 3α-hydroxy-7-methylene-5β-cholanoic acid (1.1 g.; m.p. 104°-105° C.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cn2)cn1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=65%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(Br)cc2C1=O
Temperature: 0 °C

Procedure:
A mixture of 39.5 g of 5-bromoisatoic acid anhydride, 14.5 g of sarcosine and 150 ml of dimethyl sulphoxide is heated to 100° while stirring. After completion of the gas evolution, the mixture is stirred at 100° for a further 30 minutes and subsequently poured into 900 ml of ice-water. The precipitated crystals are filtered off under suction, washed with water and dried at 50° in vacuo over phosphorus pentoxide. There is obtained 7-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione as light beige crystals. A sample recrystallized from methanol has a melting point of 260°-261°.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[N+:30]([C:33]1[CH:34]=[C:35]([CH2:39][CH:40]=[O:41])[CH:36]=[CH:37][CH:38]=1)([O-:32])=[O:31]>ClCCl>[N+:30]([C:33]1[CH:34]=[C:35]([CH2:39][CH:40]([C:6]2[N:7]=[CH:8][N:9]([C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:10]=2)[OH:41])[CH:36]=[CH:37][CH:38]=1)([O-:32])=[O:31]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=CCc1cccc([N+](=O)[O-])c1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CC(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Reaction time: 1 h

Procedure:
At ambient temperature, 4.2 ml of 3M ethylmagnesium bromide are poured into 5.48 g of 4-iodo-1-trityl-1H-imidazole dissolved in 30 ml of dichloromethane. After 1 hour, 1 g of the product obtained in Step 1 is dissolved in 20 ml of dichloromethane. After hydrolysis with a saturated solution of ammonium chloride, extraction with dichloromethane, and then washing the organic phase with water, the solvent is evaporated off and the residue is purified by chromatography on silica gel, using as eluant a 98/2 dichloromethane/methanol mixture.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)=[O:5])C.Cl>>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH:7]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1c1ccsc1
Agent: Cl
Product: O=C(O)C1CCN(Cc2ccccc2)CC1c1ccsc1

Procedure:
The product from step c) (4.78 g, 14.5 mmol) was treated with 4 M HCl at 100° C. for 16 hours. Next, the reaction was evaporated to dryness, azeotroped with toluene (2×50 ml) and placed on the high vacuum to give the subtitle compound. MS calculated for C17H19NO2S−H 300, observed 300.
Reaction SMILES: [CH3:1][C:2](CCC1C=CC2C=C(OC)C=CC=2C=1)=[O:3].[C:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:32][CH3:33])[C:27]=2[Br:31])[CH:22]=1)(=[O:20])[CH3:19]>>[Br:31][C:27]1[C:26]([O:32][CH3:33])=[CH:25][CH:24]=[C:23]2[C:28]=1[CH:29]=[CH:30][C:21]([C:18]([OH:20])=[CH:19][C:2](=[O:3])[CH3:1])=[CH:22]2
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Reactant: COc1ccc2cc(CCC(C)=O)ccc2c1
Product: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br

Procedure:
New process for the synthesis of the antiinflammatory drug known as nabumetone that consists in reacting 2-acetyl-5-bromo-6-methoxynaphthalene with an alkyl acetate in presence of an alkaline alcoholate to get 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one that by catalytic hydrogenation in a polar solvent and in presence of a base gives 4-(6-methoxy-2-naphthyl)butan-2-one known as nabumetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH:12]([C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[C:20]=1[NH2:21])([CH3:14])[CH3:13].N1C=CC=CC=1.O>ClCCl>[CH:22]([C:19]1[CH:18]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[C:20]=1[NH:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:23])[CH3:24]
Reactant: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1N
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(C(=O)Nc2c(C(C)C)cc(-c3ccccc3)cc2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A solution of 3-methoxybenzoyl chloride (7.54 mL, 55.3 mmol) in DCM (dichloromethane) (50 mL) was added slowly to a 0° C., stirred solution of 3,5-diisopropyl-[1,1′-biphenyl]-4-amine (10 g, 39.5 mmol) and pyridine (5.43 mL, 67.1 mmol) in DCM (100 mL). The mixture was then warmed up and stirred overnight at room temperature. After the reaction was complete, water was added into the reaction mixture. The aqueous mixture was extracted with DCM, and the DCM layer was separated, washed with water (2×), aq. Na2CO3, water (2×) and brine, and dried over anhydrous Na2SO4. Filtration and evaporation gave an off-white solid which was recrystallized from hexane/DCM (2/8) (v/v) to afford a snow white solid (9.93 g, 65%).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:8][C:9]2[C:10]([CH2:15]O)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[C:33]([NH:40][CH2:41][CH2:42][SH:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[C:23]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[S:8][C:9]2[C:10]([CH2:15][S:43][CH2:42][CH2:41][NH:40][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: OCc1ncccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)NCCSCc1ncccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
Into a 3 L round bottom flask equipped with a mechanical stirrer, thermometer and nitrogen purge was charged 3-triphenylmethylthio-2-hydroxymethylpyridine (40.0 g, 0.104 mol, 1 eq.) followed by DMF (1.2 L). The solution was cooled to 0° C. and a pre-formed solution of thionyl chloride (12.4 g, 0.104 mol, 1.0 eq.) in DMF (200 mL) was charged dropwise over approximately 5 minutes. To this orange coloured solution was charged BOC-cysteamine (18.4 g, 0.104 mol, 1 eq.) followed by finely powdered potassium carbonate (43.1 g, 0.104 mol, 1 eq) and the resulting suspension was vigorously stirred for two hours until TLC analysis showed reaction completion (1:1 EtOAc/hexanes). The solution was poured into a 3 L of a 4:1 mixture of ice water/4:1 ethyl acetate-hexane. The aqueous was separated and extracted with an additional 200 mL of 4:1 ethyl acetate-hexane. The organics were combined and washed with water (2×200 mL) then brine (2×200 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was removed in vacuo to give 54 grams of a brown oil. This oil was purified by column chromatography on silica gel to give 41 grams of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 1.41 (s, 9H); 2.77 (t, 2H); 3.42 (t, 3H); 4.11 (s, 2H); 7.05-7.45 (m, 16H); 8.22 (d, 1H); 8.65 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:36][CH2:35][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[N:28]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]4[N:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:20]=4[CH:19]=3)[C:12]2=[O:34])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:38]([O:40][CH2:41][C:42]([Cl:45])([Cl:44])[Cl:43])=[O:39].[NH4+].[Cl-]>CC#N>[Cl:43][C:42]([Cl:45])([Cl:44])[CH2:41][O:40][C:38]([N:8]1[CH2:36][CH2:35][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[N:28]([CH2:29][C:30]([CH3:32])([CH3:33])[CH3:31])[C:21]4[N:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:20]=4[CH:19]=3)[C:12]2=[O:34])[CH2:10][CH2:9]1)=[O:39]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)Cn1c(CN2C(=O)OC3(CCN(Cc4ccccc4)CC3)C2=O)cc2cnc(C#N)nc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)Cn1c(CN2C(=O)OC3(CCN(C(=O)OCC(Cl)(Cl)Cl)CC3)C2=O)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of 0.22 g (0.45 mmoles) of 6-(8-benzyl-2,4-dioxo-1-oxa-3,8-diaza-spiro[4.5]dec-3-ylmethyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 4 ml of CH3CN is added 2,2,2-trichloroethyl chloroformate(0.91 mmol) at ambient temperature and the mixture is stirred for 18 hours. Aqueous NH4Cl is added and the organic layer is extracted with AcOEt, washed with brine, dried over Na2SO4 and concentrated. The crude product is purified by silica gel column chromatography (n-Hexane:AcOEt=1:1) to give 0.25 g of 3-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2,4-dioxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid 2,2,2-trichloro-ethyl ester in 96% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:17]([O:19]CC)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:17]([OH:19])=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(CC1CCC1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: COc1cn(C(CC2CCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
138 mg (0.33 mmol) of ethyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 104 mg (82% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:26]([O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:27]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCOc1ccc(N)cc1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(CC)c3n2)cc1

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (3.60 mmol) of 4-ethoxyaniline was fused in a 160° C. oil bath for 10 minutes. The dark violet melt was cooled and dissolved in 1 mL of warm glacial acetic acid. This solution was diluted to 10 mL volume with water to precipitate a solid. The solid was filtered, washed well with water, and dried; wt 0.140 g. Purification was effected by filtration of an ethyl acetate solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 2 mL volume and 2 mL of petroleum ether was added. The crystals that separated on inducement were filtered and washed with ether; wt 0.094 g; mp 192°-194° C.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][C:5]#[N:6].[CH2:9]([NH2:11])[CH3:10]>CO>[CH2:9]([NH:11][C:3](=[N:4][C:5]#[N:6])[S:2][CH3:1])[CH3:10]
Reactant: CSC(=NC#N)SC
Reactant: CCN
Solvent: CO
Product: CCNC(=NC#N)SC
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of dimethyl cyanodithioiminocarbonate (2.85 g, 17.6 mmol) in methanol (20 mL) was added ethylamine (2M soln, 9.7 mL, 19.4 mmol). The solution was allowed to stir at reflux overnight. The solution was cooled to room temperature and the desired product crystallized out of solution over 2 hours. The crystals were collected on a buchner funnel, washed with cold methanol several times, and dried in vacuo to give 1-ethyl-2-methyl-3-cyanoisothiourea as a white solid (1.08 g, 43%). 1H NMR (CDCl3) δ 1.22 (t, 3H, J=6 Hz), 2.61 (s, 3H), 3.35 (s, 1H), 3.46 (q, 2H, J=6 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)C1C=CC=CC=1>CO.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][CH2:18][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[CH2:14]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc(OCc3ccccc3)cc2C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1Cc2ccc(O)cc2C1
Reaction time: 4 h
Yield: 94 %

Procedure:
Dissolved in 100 ml of methanol were 3.53 g (10.0 mmol) of 5-benzyloxy-2-(t-butoxycarbonylaminomethyl)indane. After 0.3 g of 10% palladium-carbon was added to the solution, the mixture was stirred for 4 hours under a hydrogen atmosphere. The catalyst was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain 2.79 g of a colorless oily substance. Yield: 94%.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2([C:13]3[N:14]([CH3:18])[CH:15]=[N:16][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:19]([C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[C:22]1=[O:29])[CH3:20]>>[CH2:19]([C:21]1([C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[O:36][C:2]2[CH:9]=[C:8]([C:10]3([C:13]4[N:14]([CH3:18])[CH:15]=[N:16][CH:17]=4)[CH2:12][CH2:11]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[C:22]1=[O:29])[CH3:20]
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Reactant: Cn1cncc1C1(c2ccc(C#N)c(F)c2)CC1
Product: CCC1(c2cccc(Oc3cc(C4(c5cncn5C)CC4)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
Using the procedure described in Example 3, the title compound was prepared starting with 2-fluoro-4-[1-(3-methyl-3-H-imidazol-4-yl)-cyclopropyl]-benzonitrile (as described in Step A above) (0.050 g, 0.21 mmol) and 3-ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (0.078 g, 0.21 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:3]=1
Reactant: c1nc[nH]n1
Reactant: O=Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Cl)cc1-n1cncn1
Temperature: 80 °C

Procedure:
In a microwave reaction vessel are combined 4-chloro-2-fluoro-benzaldehyde (200 mg. 1.26 mmol), 1H-1,2,4-triazole (113 mg, 1.64 mmol) and potassium carbonate (350 mg, 2.52 mmol) in DMSO (5 mL) and warmed to 80° C. for 5 minutes in a microwave. The reaction mixture is cooled to room temperature and poured into water and extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-3% MeOH/CH2Cl2) affords 4-chloro-2-1,2,4-triazol-1-yl-benzaldehyde which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]OC)[CH:9]=1.B(Cl)(Cl)[Cl:15].O>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][Cl:15])[CH:9]=1
Reactant: ClB(Cl)Cl
Reactant: COCc1csc(CC(=O)OC)c1
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc(CCl)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of (4-methoxymethyl-thiophen-2-yl)-acetic acid methyl ester (0.70 g, 3.50 mmol) in dichloromethane (20 mL) is treated with boron trichloride (3.50 mL, 1.0 M, 3.50 mmol) in a dropwise maner. After stirring at room temperature for 30 min the mixture is poured into water and extracted with dichloromethane (3×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue is purified by chromatography (silica gel, 5-10% ethyl acetate in heptane) to give (4-chloromethyl-thiophen-2-yl)-acetic acid methyl ester (0.58 g, 81%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.18 (s, 1 H), 6.95 (s, 1 H), 4.52 (s, 2 H), 3.80 (s, 2 H), 3.72 (s, 3 H).