Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.C([Li])CCC.CCCCCC.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CCOCC>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1)[CH3:40]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3c2)CC1
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)Cc1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
A solution of 2-bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (2 g, 5.5 mmol) in ether (10 mL) under nitrogen was added 1.6 M n-butyllithium in hexane (4 mL, 6.4 mmol) at 0° C. The solution was stirred for 30 min at 0° C., then treated with copper(I) bromide-dimethyl sulfide complex (0.8 g, 3.9 mmol). After 2 hrs stirring, a solution of ethyl bromoacetate (0.7 mL, 6 mmol) in ether (4 mL) was added. The solution was stirred at 0° C. for 2 hrs, then warmed to room temperature for 3 hrs. The reaction was quenched with 10% HCl aqueous then the insoluble was filtered off. The organic layer was washed with water, sodium bicarbonate aqueous, dried over MgSO4, filtered and concentrated. The crude was purified via silica gel column eluted with EtOAc in hexanes from 0 to 10% to give light yellow solid (0.45 g, yield: 22% yield). ESI-MS: 369.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:19]5=[N:24][N:25]([CH2:27][C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)[CH:26]=[C:18]5[CH:17]=[C:16]([CH3:36])[C:15]=4[N:14]=3)=[CH:11][C:10]([O:37][CH3:38])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1>O1CCCC1.C(N)(C)C>[CH:12]([NH:8][C:21]([C:20]1[C:19]2[C:18](=[CH:26][N:25]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:24]=2)[CH:17]=[C:16]([CH3:36])[C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([O:37][CH3:38])[CH:11]=1)=[O:22])=[O:23])([CH3:13])[CH3:11]
Reactant: COc1ccc(Cn2cc3cc(C)c4nc(-c5cc(OC)nn5-c5ncccc5Cl)oc(=O)c4c3n2)cc1
Solvent: C1CCOC1
Solvent: CC(C)N
Product: COc1ccc(Cn2cc3cc(C)c(NC(=O)c4cc(OC)nn4-c4ncccc4Cl)c(C(=O)NC(C)C)c3n2)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-2-(4-methoxy-benzyl)-5-methyl-2H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one (0.100 g, 0.189 mmol) in tetrahydrofurane (2 ml) was treated with 16 drops of isopropyl amine and stirred at 20° C. for three hours. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel using a mixture of 75% ethyl acetate 25% cyclohexane. The desired product showed the physical data reported in the corresponding table (P.34.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH:27](OCC)OCC)=[CH:25][N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OC(C)=O)=O.[N:41]1[CH:46]=CC=C[CH:42]=1.CNC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH2:27][N:41]([CH3:46])[CH3:42])=[CH:25][N:24]=[N:23]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)c1cnnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: c1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CN(C)Cc1cnnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 30 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(5-diethoxymethyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure Q, 1.0 g, 2.0 mmol) and Ac2O/pyridine (1:2 v/v, 6 mL), and stirred at room temperature for 4 hours. The reaction mixture was subsequently diluted with Et2O and washed with 1 M HCl, saturated NaHCO3, and brine. The combined organics were then dried over Na2SO4 and concentrated in vacuo. The resultant product (35 mg, 0.075 mmol) and dimethyl amine (80 μL, 2.0 M in THF) were combined in a 4 mL scintillation vial and stirred for 30 minutes. NaBH(OAc)3 (32 mg, 0.17 mmol) was then added and the reaction was stirred for 12 hours at room temperature. The reaction mixture was subsequently diluted with Et2O, washed with 1 M HCl, and the combined organics were purified by preparative TLC to generate 4-tert-butyl-N-[4-chloro-2-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)phenyl]-benzenesulfonamide: MS (ES) M+H expected 448.2, found 448.4.
Reaction SMILES: [NH4+].[OH-].C([S:11][CH:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH:13]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])(=O)C1C=CC=CC=1>O>[SH:11][CH:12]1[C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][CH:13]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20]
Reactant: CC1(C)CCC(C(=O)N2CCC[C@H]2C(=O)O)C1SC(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C(=O)N2CCC[C@H]2C(=O)O)C1S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Water (27 ml) and 32% NH4OH (18 ml) are added to the trans diastereoisomer of 1-[(2-benzoylthio-3,3-dimethylcyclopentyl)carbonyl]-L-proline (5.25 g) characterized by m.p. 153° C. kept under Argon atmosphere. The reaction mixture is stirred at room temperature for 21/2 hours then an aqueous solution saturated with (NH4)2SO4 (45 ml) is added and the mixture is stirred at 0°-5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:49]=[CH:48][CH:47]=[CH:46][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([CH:28]=[N:29][NH:30][C:31](=O)[CH2:32][CH2:33][N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44])C(=O)CCN1C(=O)C2C(=CC=CC=2)C1=O)=[O:5].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:49]=[CH:48][CH:47]=[CH:46][C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:28]=[N:29][N:30]=[C:31]1[CH2:32][CH2:33][N:34]1[C:42](=[O:43])[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:36]2[C:35]1=[O:44]
Reactant: O=C(CCN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CCN1C(=O)c2ccccc2C1=O)c1ccccc1C(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1Cl)c1ccccc1-n1cnnc1CCN1C(=O)c2ccccc2C1=O

Procedure:
The 1,3-dioxo-2-isoindolinepropionic acid, [[N-[2-(o-chlorobenzoyl)phenyl]-1,3-dioxo-2-isoindolinepropionamido]methylene]hydrazide from Preparation 5A is mixed with toluene (165 ml.), treated with trifluoroacetic acid (0.732 ml.) and warmed, under nitrogen, at 100°-110° C. for 1.5 hours. The mixture is concentrated in vacuo and the residue is mixed with cold, dilute sodium bicarbonate and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel (200 g.) with 2% methanol-98% chloroform. The product thus obtained is crystallized to give 2'-chloro-2-[3-(2-phthalimidoethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:30]([C:29]2[CH:33]=[CH:34][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=2)=[O:31])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(C(C)=O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) and commercially available 4-acetylbenzoic acid (46 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (87 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was then purified in the same manner as described in Example 50 to obtain 43 mg of the title compound (yield: 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:31]=1)[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:31]=[C:6]([C:7]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)=[N:16]3)=[C:10]([CH3:11])[N:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cncc(Br)c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cncc(Br)c4)n3n2)cc(OC)c1OC
Yield: 7.5 %

Procedure:
In a similar manner as described for Example 9, 5-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)nicotinamide (Intermediate 20) (0.15 g, 0.31 mmol) and 1,2,4-triazole (128 mg, 1.9 mmol) in pyridine (4 mL) and phosphorus oxychloride (0.087 mL, 0.93 mmol) gave 7-(5-bromopyridin-3-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.011 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.81-9.78 (m, 1H), 9.18 (s, 1H), 8.93-8.90 (m, 1H), 8.73-8.70 (m, 1H), 8.57 (s, 1H) 7.12 (s, 2H), 3.73 (s, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 2.59 (s, 3H). MS m/z 471, 473 (M+1, M+3).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:24]2[S:28][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]3)=[N:26][CH:25]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1)=[O:5])[CH3:2].[Li+].[OH-].Cl>O1CCCC1.CO>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:24]2[S:28][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]3)=[N:26][CH:25]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(=O)OCC)CC3)s2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(=O)O)CC3)s2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of ethyl 4-[5-(3-[(ethylcarbamoyl)amino]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (2.030 g, 3.70 mmol) in tetrahydrofuran (13.45 mL) and methanol (5.045 mL) was added aqueous 1N LiOH (11.10 mL, 11.10 mmol). The resulting solution was stirred 2 h at room temperature and 2 h at 50° C. The reaction was cooled to ambient temperature and was then quenched with HCl (11.10 mL, 11.10 mmol) and then diluted with aqueous 25% NH4OAc (to pH=7). The mixture was extracted with 2-Me-THF. The combined organic fractions were washed with brine, dried (Na2SO4), and filtered. The solvent was evaporated under reduced pressure and the resultant residue was purified by column chromatography on silica gel (Combiflash, 0-100% ethanol in dichloromethane) to give a brown oil-solid. The residue was triturated in hot ethyl acetate. Diethyl ether was added and the product was isolated by filtration. The solid was dried to give 4-[5-(3-[(ethylcarbamoyl)amino]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (396 mg, 0.741 mmol, 20.02% yield) as a mixture of the syn and anti diastereoisomers. MS APCI: [M+H]+ m/z 535.1.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:19]3[C:27]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])[CH:9]=2)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:59][C@@H:60]1[CH2:64][CH2:63][NH:62][CH2:61]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:2][C:3]1[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:19]3[C:27]([CH2:28][CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([N:62]3[CH2:63][CH2:64][C@@H:60]([F:59])[CH2:61]3)=[O:22])[CH:9]=2)[N:4]=1
Reactant: F[C@@H]1CCNC1
Reactant: CC(C)(C)CCc1cccc(C(=O)O)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)CCc1cccc(C(=O)N2CC[C@@H](F)C2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbutyl)benzoic acid hydrochloride (168 mg, 0.357 mmol) and HATU (204 mg, 0.536 mmol) in DMF (5 mL) was stirred for 10 min at RT. (R)-(−)-3-fluoropyrrolidine hydrochloride (224 mg, 1.787 mmol) and 1,1′-dimethyltriethylamine (0.622 mL, 3.57 mmol) were added and the reaction mixture was allowed to stir overnight at RT. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (10-100% water with 0.1% TFA/CH3CN, 11 min). The obtained product was eluted on an SCX cartridge with MeOH followed by 2M NH3/MeOH. The basic fraction was concentrated to afford the titled compound as a white solid. MS (ESI, pos. ion) m/z: 505 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[I:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Yield: 29.3 %

Procedure:
A suspension of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile (9.8 g) and N-iodosuccinimide (8.87 g) was heated at reflux in carbon tetrachloride for 3.5 hours, cooled and washed with sodium bisulfite solution, NaOH solution and water. The dried (magnesium sulfate) solution was evaporated and purified by chromatography on silica gel eluting with dichloromethane to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-iodo-1H-pyrazole-3-carbonitrile (4.0 g), m.p. 212-214 ° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28](I)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50](B2OC(C)(C)C(C)(C)O2)[C:49]([CH3:62])=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:50]5[C:49]([CH3:62])=[N:48][N:47]([CH2:46][C:45]6[CH:63]=[CH:64][CH:65]=[C:43]([F:42])[CH:44]=6)[C:51]=5[CH3:52])=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(I)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)c(NS(C)(=O)=O)c3)cc12
Yield: 2.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 50) (200 mg, 0.286 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (123 mg, 0.373 mmol) in sodium carbonate (90 mg, 0.858 mmol), Pd(PPh3)2Cl2 (10 mg, 0.0143 mmol), Toluene/ethanol/water (5/5/2.5 ml) to afford 6 mg (2.7% yield) of titled compound. MS: m/z=774.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[N:21][CH:20]=2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][C:22]([C:24]([NH:26][C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1F
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3F)cc2)o1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 1, using 4-chloro-2-fluoro-1-isocyanatobenzene (0.533 mmol) and intermediate 1. 1H-NMR (DMSO-d6, 300 MHz): δ 9.356 (s, 1H), 9.017-8.990 (d, 1H), 8.733 (s, 1H), 8.208-8.149 (m, 1H), 7.826 (s, 1H), 7.809-7.780 (d, J=8.7 Hz, 2H), 7.623-7.593 (d, J=9 Hz, 2H), 7.514-7.470 (d, J=2.1, 11.1 Hz, 1H), 7.270-7.241 (dd, J=0.6, 8.7 Hz, 1H), 4.328-4.277 (m, 1H), 3.680 (s, 3H), 2.286-2.217 (m, 1H), 0.979-0.957 (d, J=6.6 Hz, 6H); MS (ESI) m/z 487 (M−H), 489 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH2:8]=[O:9]>>[CH3:1][C:2]([CH2:5][CH2:6][CH3:7])([CH2:8][OH:9])[CH2:3][OH:4]
Reactant: CCCC(C)C=O
Reactant: C=O
Product: CCCC(C)(CO)CO

Procedure:
is a known synthetic perfume obtainable from 2-methyl pentanal 23 (cf. following scheme). The educt 23 is reacted with 2 equivalents of formaldehyde in a crossed Canizzaro reaction to form 2-methyl-2-propylpropane-1,3-diol 24. The diol 24 may then be acetalized with 2-methylpentanal 23 to form Troënan® 22.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:25]([O:27]CC)=[O:26])[C:7](=[O:24])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([NH2:22])=[C:17]([Cl:23])[CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:25]([OH:27])=[O:26])[C:7](=[O:24])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:16]=[C:17]([Cl:23])[C:18]([NH2:22])=[C:19]([Cl:21])[CH:20]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(Cl)c(N)c(Cl)c3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2cc(Cl)c(N)c(Cl)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-amino-3,5-dichloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (140 mg, 0.326 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (55 mg, 1.31 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 29 as yellow solid (90 mg, 69%). ESI-MS m/z: 403 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.30 (d, J=7.5 Hz, 1H), 8.25 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.57 (s, 2H), 6.12 (s, 2H), 2.92 (s, 3H), 2.54-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.84-0.83 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:9][N:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])=[O:8]>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH:13]([CH3:14])[CH2:12][CH:11]=[N:10]1)=[O:8]
Reactant: C/C=C/C=NNC(=O)c1cnccn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC1CC=NN1C(=O)c1cnccn1
Reaction time: 3 h
Yield: 36.8 %

Procedure:
A quantity of 3.8 g of this hydrazone was suspended in 10 ml of diphenyl ether, followed by stirring at 200°-220° C. (bath temperature) for 3 hours. After cooling, the reaction liquid was purified by silica gel column chromatography (ethyl acetate). Thus there was obtained 1.4 g of 1-pyrazinylcarbonyl-5-methyl-2-pyrazoline (mp. 77°-79° C.). The yield was 36.8%.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]([Cl:28])[C@H:13]3[OH:29])[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]([Cl:28])[C@H:13]3[O:29][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](OS(C)(=O)=O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 1 h

Procedure:
A mixture of 1.76 g of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione, 1.11 ml of methanesulfonyl chloride and 5.2 ml of pyridine was stirred for 1 hour under ice cooling, and then for 12 hours at room temperature. Ice-cooled water was added to the reaction mixture, and the precipitated crystals were collected by filtration to give 2.01 g of 17α-acetoxy-6β-chloro-7α-mesyloxy-2-oxa-4-pregnene-3,20-dione.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[O:23][CH:24]=1>>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1/[CH:26]=[CH:25]/[C:22]1[O:23][CH:24]=[C:20]([CH2:19][O:15][C:11]2[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)[CH:14]=[CH:13][CH:12]=2)[N:21]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: Oc1cccc(CCCn2ccnn2)c1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccc(/C=C/c2nc(COc3cccc(CCCn4ccnn4)c3)co2)c(F)c1
Yield: 86.5 %

Procedure:
Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol (143 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188 mg), the same reaction as Example 2 was carried out to yield the titled compound (257 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]([OH:24])[CH2:9][O:10][CH2:11][C:12]([F:23])([F:22])[C:13]([F:21])([F:20])[C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:25][C:26](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:27]>>[C:26]([O:24][CH:8]([CH2:9][O:10][CH2:11][C:12]([F:22])([F:23])[C:13]([F:21])([F:20])[C:14]([F:18])([F:19])[CH:15]([F:16])[F:17])[CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:27])[CH3:25]
Reactant: OC(COCC(F)(F)C(F)(F)C(F)(F)C(F)F)CN1CCOCC1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CC(=O)OC(COCC(F)(F)C(F)(F)C(F)(F)C(F)F)CN1CCOCC1
Temperature: 50 °C
Reaction time: 10 h
Yield: 273.1 %

Procedure:
To 37.5 g of 1-morpholino-3-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-2-propanol was added 11.2 g of acetic anhyride. The mixture was stirred at 50° C. for 10 hours, followed by conventional aqueous work-up and purification by silica gel column chromatography. There was obtained 39.6 g of 2-morpholino-1-{(2,2,3,3,4,4,5,5-octafluoropentyloxy)-methyl}ethyl acetate (yield 95%).