Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][C@@H:10]1[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl.C(OCC)(=O)C>N1C=CC=CC=1>[C:24]([O:15][CH:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(O)CC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(1R*,2S*)-N1,N2-Bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (Stereoisomer B) (1.74 g) was dissolved in pyridine (15 ml), and acetic anhydride (5 ml) was added to stir the mixture at room temperature for 4 days. 1N Hydrochloric acid was added to the reaction mixture, extraction was conducted with ethyl acetate, and the resultant organic layer was successively washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3) to obtain the title compound (1.96 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH:10]([O:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([O:13][CH:10]([CH3:12])[CH3:11])[NH:18][N:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Yield: 68.9 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (533 mg, 2.93 mmol), 5-isopropoxy-1H-pyrazol-3-amine (413 mg, 2.93 mmol) and triethylamine (0.49 ml) in THF (5 ml) was stirred at room temperature for 10 hours. Solvent was removed and EtOAc was added. The solution was washed with water and dried over anhydrous sodium sulfate and was concentrated to give title compound as a white solid (582 mg, 69%). LC-MS, 246 (M-42); 1H NMR (CDCl3) δ 8.19 (s, 1H), 7.80 (s, 1H), 5.79 (s, 1H), 4.65 (m, 1H), 1.30 (d, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:24]([F:27])([F:26])[F:25])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5](=[O:23])[NH:4]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O.CN(C=O)C>[Br:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:5](=[O:23])[NH:4][C:3]2([CH2:2][NH:1][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=1)[C:24]([F:26])([F:27])[F:25]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(CN2C(=O)NC(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)NC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of DMF (5 mL) containing 4-(aminomethyl)-6-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (710 mg, 1.60 mmol), 4-fluorobenzoic acid (246 mg, 1.76 mmol), hydroxybenzotriazole monohydrate (245 mg, 1.60 mmol) and triethylamine (0.22 mL, 1.6 mmol) at 0° C., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.9 mmol) was added little by little thereto. After the reaction solution was stirred overnight at room temperature, water was slowly added thereto under stirring. After a solid began to precipitate, further excess water was added thereto, and the mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed with water and then dried under reduced pressure, whereby the objective compound (815 mg, 90%) was obtained as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2].C(O)C.O.[C:20]1([C@H:26]([OH:31])[C@@H:27]([NH2:30])[CH2:28][OH:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[C:20]1([C@H:26]([OH:31])[C@@H:27]([NH2:30])[CH2:28][OH:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C(=O)O
Agent: N[C@@H](CO)[C@@H](O)c1ccccc1
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
100 g N-acetyl-indoline-2-carboxylic acid (purity 96.5%) was dissolved in 835 ml of a mixture containing 90% ethanol (EtOH), 5% water and 5% methanol (MeOH), with heating to 60° C., and with mechanical stirring. 54.4 g/0.69 eq. (1S,2S)-1-phenyl-2-amino-1,3-propanediol ([α]20D =+25.7° (c=1, MeOH)) was dosed in portions in 30 min. at 60° C. At the end spontaneous crystallization of the salt took place. After 30 minutes' subsequent stirring at 60-66° C., cooling to 15° C. took place, followed by another 30 minutes' stirring. After filtration over a P4 glass filter, three washings with 120 ml EtOH took place. After air-drying, 68.9 g off-white (S)-N-acetyl-indoline-2-carboxylic acid-(1S,2S)-1-phenyl-2-amino-1,3-propanediol salt was obtained, corresponding to a yield of 37.8%. Enantiomeric excess=96.3% (chiral HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(OC([CH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=O)=O)C.O.[CH2:21]([OH:23])C>C1(C)C(C)=CC=CC=1>[C:14]1([N:1]2[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[NH:4][C:21]2=[O:23])[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: Nc1ccccc1N
Reactant: CCO
Reactant: CCOC(=O)C1CCCC1=O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1=CCCC1

Procedure:
100 mmol of 2-aminoaniline and 135 mmol of 2-ethoxycarbonylcyclopentanone in 50 ml of xylene are brought to reflux for 5 hours, the water and the ethanol formed being removed with the aid of a Dean and Stark apparatus. After cooling, the expected product crystallizes and it is then filtered, washed with xylene and then with hexane and then dried.
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([OH:36])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=[C:19]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([OH:52])[C:46]([CH3:54])([CH3:53])[CH2:45]3)[N:18]=2)[CH2:6][C:5]1([CH3:56])[CH3:55].S([O-])([O-])=O.[Na+].[Na+].[C:63]([OH:67])([CH3:66])([CH3:65])[CH3:64]>O.C(OCC)(=O)C>[OH:67][C:63]([CH3:66])([CH3:65])[CH2:64][O:52][N:47]1[C:46]([CH3:54])([CH3:53])[CH2:45][CH:44]([CH2:43][CH2:42][CH2:41][CH2:40][NH:39][C:19]2[N:18]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:7]3[CH2:6][C:5]([CH3:56])([CH3:55])[N:4]([O:3][CH2:64][C:63]([CH3:66])([OH:67])[CH3:65])[C:9]([CH3:11])([CH3:10])[CH2:8]3)[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:34])([CH3:35])[N:31]([O:36][CH2:64][C:63]([CH3:66])([OH:67])[CH3:65])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=2)[CH2:49][C:48]1([CH3:51])[CH3:50]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Temperature: 60 °C
Yield: 37.2 %

Procedure:
A solution of 40 g (0.35 mol) of 30% aqueous hydrogen peroxide is added over 1.25 hours to a mixture of 11.7 g (0.011 mol) of 2,4,6-tris[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl]butylamino)-s-triazine and 3.0 g (0.015 mol) of ferrous chloride tetrahydrate in 100 g of tert-butyl alcohol and 9 g of water. The reaction temperature is maintained at 60-65° C. during the peroxide addition. Two equal portions (2 g, 0.29 mol) of 50% aqueous hydrogen peroxide are added to the reaction mixture while the temperature is maintained at 60° C. for 9.5 hours. After the reaction mixture is diluted with ethyl acetate and cooled to room temperature, a solution of 100 g of 20% aqueous sodium sulfite is added. The reaction mixture is heated at 60° C. for one hour to decompose the excess peroxide. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are concentrated. The crude product is purified by flash chromatography on silica gel with 2:1 (v/v) cyclohexane/ethyl acetate to afford a material which is triturated with 1:1 (v/v) cyclohexane/acetone to give 4.0 g of the title compound as a white solid, melting at 172-176° C.
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH:9]=[CH:10][CH:3]1[CH:4]1[CH:7]2[N:6]=[N:5]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[N+:19]=[N-:20])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[N:19]=[N:20][CH:9]3[C:10]42[CH:2]([OH:1])[CH:8]3[CH:7]2[CH:4]([N:5]=[N:6]2)[CH2:3]4)=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1
Reactant: OC1C2C=CC1C1N=NC21
Solvent: Cc1ccccc1
Product: OC1C2C3N=NC3CC13C2N=NN3c1ccc(Cl)cc1

Procedure:
30 parts of 9-hydroxy-3,4-diazatricyclo[4,2,1,02,5 ]-nona-3,7-diene and 34 parts of p-chlorophenyl azide in 100 parts of toluene were heated at 80° C. for 3 hours, while stirring. The mixture was evaporated down in a rotary evaporator at from 20° to 40° C. and under 20 mbar, after which the residue was digested successively with 100 parts of diethyl ether and 100 parts of petroleum ether, and the product was dried at 20° C. under 1 mbar. 59 parts (92 mole %) of 8-(4-chlorophenyl)-12-hydroxy-3,4,8,9,10-pentazatetracyclo[5,4,1,02,5,07,11 ]dodeca-3,9-diene of melting point 178° C. (decomposition) were obtained (Command No. 1). ##STR20##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2cccc(Br)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(c2cccc(Br)c2)CC1
Temperature: 50 °C
Yield: 86 %

Procedure:
To a solution of ethyl 1-(3-bromophenyl)piperidine-4-carboxylate (5.6 g, 18 mmol) in THF/MeOH (360 mL, 1:1), was added a solution of NaOH (1M, 90 mL) at rt. The mixture was heated at 50° C. for 30 min and organic solvent was removed under reduced pressure. The water solution was mixed with ice and 1M HCl (90 mL) and extracted with dichloromethane/methanol. The combined organic phase was dried over unhydrous Na2SO4 and evaporated. The residue was solidified with dichloromethane/hexane to give the titled compound (4.4 g, 85%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[N:7]=[C:8]([NH:22][NH2:23])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=[O:4].C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43]C)=[O:41]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[N:7]=[C:8]([NH:22][NH:23][C:40]([O:42][CH3:43])=[O:41])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:10]=1[CH3:11])=[O:4]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(NN)=NC1c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NNC1=NC(c2ccc(C#N)cc2)C(C(=O)OC)=C(C)N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
Intermediate 2 (724 mg, 1.7 mmol) was dissolved in THF (20 mL) and cooled to 0° C. before addition of triethylamine (362 μL, 2.6 mmol) and ethyl chloroformate (191 μL, 2 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resultant residue was triturated with EtOAc, filtered and the solid collected to yield the title compound as a white solid (49 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[OH:19])[NH2:15])#[N:11]>CO.O>[OH:19][C:18]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:18]([OH:19])=[C:12]([C:10]#[N:11])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[C:10]#[N:11]
Reactant: N#Cc1cc(N)ccc1O
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: N#Cc1cc(Nc2ncc(F)c(Nc3ccc(O)c(C#N)c3)n2)ccc1O
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-cyano-4-hydroxyaniline (241 mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(4-hydroxy-3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.96 (d, 1H, J=3.5 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.79 (d, 1H, J=3.0 Hz), 7.71 (dd, 1H, J=3.0, 8.8 Hz), 7.54 (dd, J=3.0, 8.8 Hz), 6.94 (d, 1H, J=8.8 Hz), 6.84 (d, 1H, J=8.8 Hz); LCMS: purity: 97.2%; MS (m/e): 362.98 (M+, 100).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@:25]([OH:40])([C@H:32]([S:34][CH:35]([CH2:38]O)[CH2:36][OH:37])[CH3:33])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:40])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[C@H:32]([S:34][C@@H:35]1[CH2:36][O:37][C@@H:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[S:11][CH:12]=[CH:13][N:14]=3)=[O:8])=[CH:15][CH:16]=2)[O:2][CH2:38]1)[CH3:33]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=Cc1ccc(C(=O)Nc2nccs2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3nccs3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 1(2), a reaction was carried out using 4-formyl-N-(2-thiazolyl)benzamide, obtained in Example 27(1) (200 mg, 0.86 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (270 mg, 0.75 mmol) and p-toluenesulfonic acid monohydrate (357 mg, 1.88 mmol) and the reaction mixture was treated using a similar procedure to that described in Example 1(2) to afford the trans isomer of the title compound (64 mg, yield 15%) as a white oil and the cis isomer (29 mg, yield 7%) as a colorless oil. The trans isomer was recrystallized from tetrahydrofuran-hexane to give white powdery crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH:38]=[CH:37][N:36]=[CH:35]5)[CH:29]=4)[CH2:25][C:24](=[O:39])[NH:23][C:9]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4-(4-fluoro-phenylethynyl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K33) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (89 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cn(-c2ccc(C(=O)Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.3 %

Procedure:
To a suspension of 4-(4-methylimidazol-1-yl)benzoic acid (0.80 g) in dichloromethane (25 ml) was added oxalyl chloride (0.50 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure to yield 4-(4-methylimidazol-1-yl)benzoyl chloride (1.02 g), which was utilized without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[CH:61]=[CH:62][C:63]2[S:67][C:66]([CH2:68]O)=[CH:65][C:64]=2[CH:70]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:68][C:66]2[S:67][C:63]3[CH:62]=[CH:61][C:60]([CH3:59])=[CH:70][C:64]=3[CH:65]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc2sc(CO)cc2c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cc3cc(C)ccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (5-methyl-1-benzothien-2-yl)methanol (0.75 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid 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 a colorless solid (0.63 g, 44%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:8]=2)[CH2:5][CH2:4][CH:3]=[CH:2]1.C(N(CC)CC)C.[C:30](Cl)(=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:32]([O:31][C:30]([N:20]1[CH2:19][CH2:18][N:17]([C:9]2[N:8]=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH:3]=[CH:2]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:22][CH2:21]1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CC(Oc2nc(N3CCNCC3)nc3ccccc23)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2nc(OC3C=CCC3)c3ccccc3n2)CC1

Procedure:
To a solution of 4-[(cyclopent-2-en-1-yl)oxy]-2-(1-piperazinyl) quinazoline (1.47 g) in dry methylene chloride (15 ml) is added triethylamine (1.39 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (0.75 ml) in dry methylene chloride (3 ml). The mixture is stirred at 0° C. for 4 hours, and the reaction mixture is diluted with chloroform and washed with water, and then dried over anhydrous magnesium sulfate. The resulting solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(cyclopent-2-en-1-yl)oxy]quinazoline (1.85 g) as crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2Cl)nc1-c1ccccc1
Yield: 66.1 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)pentanoate (100 mg; 0.314 mmol), 2-chlorophenylboronic acid (73.6 mg; 0.471 mmol) and tetrakis(triphenylphosphine) palladium(0) (36.2 mg; 0.031 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.193 mL; 1.255 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 82 mg (66%) of the title compound. ESI/APCI(+): 395 (M+H).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[Cl:8][C:9]1[C:14]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=[CH:11][N:10]=1.O.[OH-].[Na+]>C1COCC1>[Cl:8][C:9]1[C:14]([N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:20][CH2:21]2)[C:6]([NH2:5])=[O:7])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Nc2cccnc2Cl)CC1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N(c1cccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
530 mL (6.1 mol) chlorosulphonyl isocyanate were placed in 6 L THF and cooled to −15° C. Then a solution of 1.25 kg (3.63 mol) benzyl 4-(2-chloro-pyridin-3-yl-amino)-piperidine-1-carboxylate in 7 L THF was added dropwise to this mixture within one hour such that the temperature of the reaction mixture did not exceed −7° C. The mixture was stirred for a further 90 minutes at approx. −8° C. and then 700 mL water was added dropwise within 30 minutes. The mixture was stirred for another 30 minutes at approx. 10° C. and then slowly combined with 8.1 L sodium hydroxide solution (2 mol/L). The reaction mixture was then heated to 50° C. and the phases were separated. The organic phase was washed with 2 L water. Then 10 L solvent were distilled off from the organic phase, 15 L butyl acetate were added to the residue and another 8 L were distilled off. By slow cooling to 0° C. the product was crystallised. The precipitate was suction filtered, washed with 2 L butyl acetate and dried at 40° C.