Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:38][C:35]2[CH:36]=[CH:37][C:30]3[CH2:29][CH2:28][CH:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:33][CH2:32][C:31]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: CS(=O)(=O)NC1CCCCC1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl
Reaction time: 0.17 h

Procedure:
Into a microwave vial was placed N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (1.0E2 mg, 0.00029 mol) and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (0.080 g, 0.00032 mol) in isopropyl alcohol (4.0 g, 0.066 mol). To this mixture was added 4N HCl-dioxane (0.03 g, 0.0003 mol) and the contents subjected to microwaves at 120° C. for 10 min. The mixture was resubjected to the same conditions for an additional 15 min. for complete conversion of starting materials. A solid had precipitated out of solution and was redissolved in methylene chloride and washed with sat. aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to a tan foam. The solid was dried at 50° C. in a vacuum oven overnight to give N-{(1R,2R)-2-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide isolated as a mixture of diasteromers as a beige foam (72 mg, 44% yield). 1HNMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.92 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.35 (t, 1H, J=8.34), 7.18 (dd, 1H, J=5.05, 8.6 Hz), 6.97 (d, 1H, J=8.1 Hz), 6.69 (d, 1H, J=7.6 Hz), 3.84 (m, 1H), 3.55 (broad s, 4H), 3.37 (m, 1H), 2.94 (s, 3H), 2.43-2.78 (m, 9H), 1.96-2.09 (m, 4H), 1.70 (d, 2H, J=8.6 Hz), 1.18-1.36 (m, 6H); MS (m/e) 549 (M+1).
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:5]=2[O:4]1)[CH3:2]>Cl>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@H]1Oc2cc(C(=O)OC)ccc2N(CC)C1=O
Agent: Cl
Product: CC[C@H]1Oc2cc(C(=O)O)ccc2N(CC)C1=O
Yield: 70.4 %

Procedure:
A mixture of (R)-2,4-diethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.80 g) in concentrated hydrochloric acid (30 ml) was stirred under reflux for a day. The concentrated hydrochloric acid was distilled off under reduced pressure to give (R)-2,4-diethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (1.20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)=[C:7]([CH2:9][C:10]([O:12]C)=[O:11])[CH:8]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[CH:8]=1
Reactant: COC(=O)Cc1cc(OC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)O)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To a mixture of methyl 2-[5-methoxy-2-[-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.98 g), tetrahydrofuran (4 mL) and methanol (4 mL) was added a 1N aqueous sodium hydroxide solution (4.2 mL) and the mixture was stirred at 50° C. for 15 hrs. 1N Hydrochloric acid (4.2 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.90 g, 94%) of 2-[5-methoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-136° C.
Reaction SMILES: [C:1]([NH:4][C@@:5]1([C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C@@:5]1([C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1)(=[O:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CC[C@H]1OCC[C@@]1(NC(C)=O)C(=O)NC(C)(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCO[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A solution of (2R,3S)-3-acetamido-2-allyl-N-tert-butyltetrahydrofuran-3-carboxamide (930 mg, 3.47 mmol) in dichloromethane (20 mL), was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (70 mg, 3 mol %) and 1,2-bis(diphenylphosphino)-ethane (83 mg, 6 mol %). The solution was stirred at room temperature for 30 minutes and then 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.01 mL, 6.94 mmol) was added dropwise, and the reaction was stirred overnight at room temperature. The next day, the reaction mixture was poured into water and the aqueous solution was extracted using ethyl acetate (3×). The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 50-80% ethyl acetate in dichloromethane) gave (2R,3S)-3-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)tetrahydrofuran-3-carboxamide as a colorless oil (864 mg, 63%). 1H NMR (CDCl3, 300 MHz) δ 7.01 (s, NH, 1 H), 6.10 (s, NH, 1 H), 4.38 (m, 1 H), 4.12 (m, 1 H), 4.00 (m, 1 H), 2.96 (m, 1 H), 2.02-2.18 (m, 2 H), 1.99 (s, 3 H), 1.42-1.62 (m, 3 H), 1.36 (s, 9 H), 1.22 (s, 12 H), 0.76 (m, 2 H); MS (+CI): m/z for C20H37BN2O5: expected 396.3; found 397.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Cl.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[OH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(O)c(N)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(O)c(NC(=O)c2ccncc2)c1
Temperature: 0 °C

Procedure:
A mixture of 2.5 g of a crude product of 2-amino-4-methoxyphenol, 3.2 g of isonicotinic acid chloride hydrochloride and 20 ml of pyridine was heated to reflux for 12 hours. The reaction mixture was poured into ice water, and precipitated deposits are collected by filtration. The obtained solid was dissolved in ethyl acetate, washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. Activated carbon was added thereto, followed by filtration through Celite™. The filtrate was concentrated under reduced pressure to give N-(2-hydroxy-5-methoxyphenyl)isonicotinamide.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][C:15]=2[O:28][CH:29]([CH3:31])[CH3:30])[NH:10][C:9]=1[CH3:32])=[O:7])[CH3:4].O.ClCCl>C(O)C1C=CC=CC=1>[CH2:3]([O:5][C:6]([C:8]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:25])[F:26])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][C:15]=2[O:28][CH:29]([CH3:31])[CH3:30])[NH:10][C:9]=1[CH3:32])=[O:7])[C:4]1[CH:16]=[CH:17][CH:8]=[CH:9][CH:32]=1
Reactant: CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500-mL four-necked round-bottom flask equipped with a stirrer, dropping funnel, reflux condenser with gas lead-off, a thermometer and a gas inlet are placed 100 mL benzyl alcohol and 0.937 g (0.0312 mole) sodium hydride (80% in oil) is introduced while flushing with a protective gas. The resulting suspension is then subsequently stirred for 30 minutes. Thereafter, a solution of 52.55 g (0.124 mole) (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid ethyl ester in 200 mL benzyl alcohol is allowed to run in, followed by stirring for 15 hours at 120° C. After cooling to ambient temperature, the reaction mixture is stirred with 1 L of water and 400 mL dichloromethane. After separating the phases, the aqueous phase is again stirred with 300 mL dichloromethane. The dichloromethane phases are combined and washed twice with 300 mL amounts of water. The dichloromethane phase is dried over anhydrous sodium sulfate. After filtering, the dichloromethane is distilled off on a rotary evaporator and subsequently the benzyl alcohol is distilled off under oil pump vacuum (54°-65° C./3-5 mm Hg). The distillation residue is dissolved in 600 mL hot cyclohexane and the solution is cooled to 0° C. while stirring. The precipitate obtained is filtered off with suction and subsequently washed with 100 mL n-hexane. The filter cake is then dried at 80° C. Yield: 43.9 g (72.8% of theory); mp 131° C. with a purity of 99.4 relative %.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+].S(=O)(=O)(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)CO>[CH2:17]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOc1ccc(B(O)O)cc1
Reactant: O=C(O)c1ccc(-c2ccc(I)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: OCCO
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1
Temperature: 95 °C

Procedure:
32.4 g of 4′-iodobiphenyl-4-carboxylic acid are introduced together with 25.8 g of glycol ester of 4-n-pentoxyphenylboronic acid and 15.9 g of sodium carbonate into 300 ml of ethylene glycol and, while stirring vigorously, 70 mg of PdCl2(PPh3)2 are added, and the mixture is stirred at 120° C. for 6 hours. The hot reaction mixture is cautiously poured into a mixture of 30 g of 37% strength sulfuric acid and 200 g of water, and the mixture is heated at 90-100° C. for 30 minutes. After filtration and washing with water, the crude product is dried at 80° C./100 mbar and then recrystallized from dimethylacetamide. This affords after drying 25.2 g (70%) of 4″-n-pentoxy-[1,1′:4′,1″]-4-carboxylic acid with a purity of >99%.
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[OH:39].[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4OC5C=CC=C(C)C=5N=4)=[CH:52][CH:51]=3)[C:42]=12>>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[O:39][C:33]5[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=5[N:31]=4)=[CH:52][CH:51]=3)[C:42]=12
Reactant: Nc1cc(Cl)ccc1O
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cc(Cl)ccc6o5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-chloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.246 mmol) and 2-amino-4-chlorophenol (0.035 g, 0.246 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine. The compound was formed as a pale yellow solid (0.020 g, 15%):
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:24][C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[Cl:23][C:14]1[CH:13]=[C:12]([O:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH:3]=2)[NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=2)[CH:17]=[C:16]([F:18])[C:15]=1[C:19]([F:20])([F:22])[F:21]
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Nc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 19.4 %

Procedure:
A mixture of 2-chloro-α,α,α,6-tetrafluoro-p-tolyl 3-fluoro-4-nitrophenyl ether (2.1 g, 0.006 mol), methyl (p-aminophenoxy)acetate (2.7 g, 0.015 mol) and potassium carbonate (2.0 g, 0,015 mol) in N,N-dimethyl formamide is stirred at 80° C. for 18 hours, cooled to room temperature, poured into brine and extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 20% ethyl acetate in hexanes solution gives the title product as a red oil (0.6 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](Cl)=[N:17][CH:16]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:17][CH:16]=1
Reactant: O=C(NCCCCCCCCCCCO)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: O=C(NCCCCCCCCCCCO)c1ccc(N2CCNCC2)nc1
Reaction time: 5 h

Procedure:
2.36 g of N-(11-hydroxy-1-undecanyl)-6-chloronicotinamide and 3.15 g of piperazine were suspended in 50 ml of toluene and the suspension was stirred at 120°-130° C. for 5 hrs. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to obtain quantitatively N-(11-hydroxy-1-undecanyl)-6-piperazinylnicotinamide. This compound was added under ice-cooling to 10 ml of fuming nitric acid and the mixture was stirred below 5° C. for 4 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=5:1) and recrystallized from chloroform/hexane to give 0.5 g (15%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25]([S:29](Cl)(=[O:31])=[O:30])=[CH:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O.O>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:29]([C:25]3[CH:24]=[CH:23][C:22]4[C:27](=[CH:28][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)[CH:26]=3)(=[O:31])=[O:30])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: N#Cc1cc(CN2CCC(N)C2=O)cs1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a solution of 4-(3-Amino-2-oxopyrrolidine-1-ylmethyl)thiophene-2-carbonitrile hydrochloride (0.43 g, 1.8 mmol), prepared as in EXAMPLE 122, in 10 mL of CH2Cl2 is added 7-methoxynaphthalene-2-sulfonyl chloride (0.51 g, 2 mmol) and triethyl amine (0.55 g, 5.4 mmol). After 16 hours, the solution is diluted with EtOAc and H2O. The layers are separated. The organic layer is washed with 1 N HCl, sat. NaHCO3 and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2 to afford the title compound (0.50 g, 1.22 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:27]>>[CH2:32]([O:31][C:29](=[O:30])[CH:28]([C:26]#[N:27])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:3]=1)[CH3:33]
Reactant: CCOC(=O)CC#N
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Product: CCOC(=O)C(C#N)c1cccc(C(CC(=O)c2ccnc(C)c2)c2ccccc2C)c1

Procedure:
In analogy to example 80, step 1, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and ethyl cyanoacetate was prepared the title compound as a light yellow oil, MS (ESI+): m/z=427.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@@H:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](OS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In ethyl acetate (4 ml) was dissolved (2R,3S)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (0.18 g). To the solution were added triethylamine (0.10 ml) and methanesulfonyl chloride (84 mg) under ice-cooling. The mixture was stirred for 30 minutes at room temperature, to which was added ethyl acetate (10 ml). The reaction mixture was washed with water and dried (anhydrous magnesium sulfate), followed by concentration to give (2R,3S)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol as an oily product. This product was dissolved in methanol (6 ml), to which was added a 5.6% methanol solution of sodium methylate (0.76 ml) under ice-cooling. The mixture was stirred for 30 minutes at room temperature, which was then concentrated under reduced pressure. To the concentrate was added ethyl acetate (30 ml), which was washed with water and dried (anhydrous magnesium sulfate). The solvent was then distilled off, and the residue was purified by means of a silica gel chromatography (eluent: hexane-ethyl acetate=1:2) to afford (2R,3R)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (0.15 g) as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=O.II>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:1]=[C:2]([NH2:4])[S:3][CH:5]=2)=[CH:9][CH:10]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(C)=O)cc1
Agent: II
Product: COc1ccc(-c2csc(N)n2)cc1
Reaction time: 5 h
Yield: 91.7 %

Procedure:
33.5 g of thiourea are added to 30 g of 4-methoxyacetophenone, 56 g of iodine are added and the mixture is kept at 100° C. for 5 hours. The reaction mixture is discharged onto water, powdered, washed several times with ether then with ammonia solution and finally with water, and dried. 37.8 g of 4-(4-methoxyphenyl)-thiazol-2-yl-amine of melting point 194°-205° C. are obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Si]([O:32][CH2:33][CH2:34][CH:35]=O)(C(C)(C)C)(C)C.C[N+](C)(C)C.C1COCC1>>[CH3:2][C:3]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][CH:20]([NH:23][CH2:35][CH2:34][CH2:33][OH:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC1(C)CCc2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Agent: C[N+](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCc2cc(-c3csc(N4CCC(NCCCO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The preparation is carried out starting from 1-[4-(1,1-dimethylindan-5-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 3-(tert-butyldimethylsilanyloxy)propionaldehyde. The protecting group is cleaved off by means of a 1M tetramethylammonium/THF solution: The reaction mixture was stirred at room temperature overnight and subsequently evaporated to dryness. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: C1(NS(=O)(=O)O)CCCCC1.[CH2:12]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[NH:21])[CH2:13][CH2:14][CH3:15].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[N:30]=[C:31]=[O:32]>>[CH2:12]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[N:21][C:31]([NH:30][C:24]1[C:23]([CH3:22])=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:29])=[O:32])[CH2:13][CH2:14][CH3:15]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CCCCN1CCCC1=N
Agent: O=S(=O)(O)NC1CCCCC1
Product: CCCCN1CCCC1=NC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The cyclohexylsulfamic acid salt of 1-n-butyl-2-iminopyrrolidine (15.97 g.; 0.05 mole) is converted to free base (7.01 g.; 0.05 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 7.36 g. (0.05 mole) of 2,6-dimethylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 31/2 hours and then evaporated to dryness in vacuo leaving an oily residue which crystallizes on cooling. Recrystallization from ethylacetate yields the pure product, 1-(1-n-butyl-2-pyrrolidylidene)-3-(2,6-dimethylphenyl)urea, m.p.=93°-95° C.