Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([NH2:24])[CH3:23].C1COCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH2:22]([NH:24][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19])[CH3:23]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a crude solution of intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜30 mL, ˜34 mmol) was added 2.0M ethylamine in THF (34.5 mL, 69 mmol) and T3P (50% solution in EtOAc, 33 ml, 51.8 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 300 ml of 1N NaOH and 400 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×500 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 75M Biotage™ column, eluting with a gradient of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (4.0 g, 35% yield). Rf=0.40 (15% MeOH/CH2Cl2+0.2% NH4OH), LRMS m/z Calcd for C15H25ClN2O2, 336.9, found. 337.4 (M+H) APCI; 1H-NMR (CDCl3) δ 7.54 (dd, J=8.3, 2.7 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (d, J=7.9 Hz, 1H), 6.52-6.35 (br m, 1H), 3.86 (s, 2H), 3.29-3.22 (m, 2H), 2.81-2.60 (m, 7H), 2.48 (d, J=8.3 Hz, 2H), 1.83 (br s, 4H), 1.11 (dt, J=7.3, 2.9 Hz, 3H); 13C-NMR (CDCl3) δ 176.7, 147.0, 134.2, 133.3, 131.4, 126.5, 123.8, 73.8, 73.9, 56.1, 54.1, 41.2, 35.0, 33.0, 23.6, 14.9.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].Cl>O.O1CCOCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=2)(=[O:27])=[O:26])[CH:16]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 64.6 %

Procedure:
To a solution of Na2CO3 (11.7 g, 110.7 mmol) in water (50 mL) and 1,4-dioxane (50 mL) at 60° C. was added 2-amino-4-chloro-benzoic acid (5.0 g, 29.14 mmol) followed by 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (20.15 g, 72.48 mmol) in 3 portions and heated the resulting reaction mixture at 80° C. for 4 hours. 2N HCl Was added until the reaction mixture became acidic (pH=˜2) and obtained white solid was filtered, washed with water, dried under high vacuum to obtain title compound (7.8 g) in 65% yield. MS (ES) M+Na expected 436.0, found 435.8.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][C:16](=[O:28])[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27].[C:29]([O:33][C:34]([NH:36][C@H:37]([C:51](O)=[O:52])[CH:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:28])[CH2:17][N:18]([C:51](=[O:52])[C@@H:37]([NH:36][C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[CH:38]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COC(=O)CNCc1ccccc1OC
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN(Cc1ccccc1OC)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g) was added over 5 minutes to a mixture of N-(2-methoxybenzyl)glycine methyl ester hydrochloride (1.72 g), N-(tert-butoxycarbonyl)-3,3-diphenyl-L-alanine (1.71 g), 1-hydroxybenzotriazole (0.81 g) and N,N-diisopropylethylamine (1.22 ml) in dichloromethane (40 ml). After being stirred for 3 hours at room temperature, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1) to give N-[(2S)-2-(tert-butoxycarbonylamino)-3,3-diphenylpropionyl]-N-(2-methoxybenzyl)glycine methyl ester (2.34 g) as a colorless powder.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.Cl.[CH3:12][O:13][NH2:14].CO.C[O-].[Na+]>CN(C)C=O>[CH3:12][O:13][NH:14][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: O=C(O)Cn1nnnc1S
Reactant: CON
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CONC(=O)Cn1nnnc1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-acetic acid (9.6 g) in N,N-dimethylformamide (60 ml) is added N,N'-carbonyldiimidazole (11.6 g), and the mixture is stirred at 0° C. for 1 hour. To this mixture is added a solution of methoxyamine hydrochloride (11.6 g) in a mixture of N,N-dimethylformamide (45 ml) and 4.6 N-sodium methoxide methanol solution (28.5 ml) and the whole mixture is stirred under ice cooling for 1 hour. The reaction mixture is poured onto ice water and extracted with a mixture of ethyl acetate and methyl ethyl ketone (2:1). The extract solution is washed with water, dried and concentrated in vacuum. The residue is crystallized from a mixture of acetone and ether to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester (7.73 g). mp. 175°-176° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:22][C:23]([F:29])([F:28])[S:24]([NH2:27])(=[O:26])=[O:25]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:27][S:24]([C:23]([F:29])([F:28])[F:22])(=[O:26])=[O:25])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: NS(=O)(=O)C(F)(F)F
Product: Cn1c(-c2cncc(CNS(=O)(=O)C(F)(F)F)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and trifluoromethanesulfonamide are processed according to the method described in Example 170 to give N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-C,C,C-trifluoromethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (s, 3H), 4.56 (s, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 10.16 (br. s., 1H). HRMS (ESI) m/z 429.0412 [(M+H)+ Calcd for C17H13ClF3N4O2S: 429.0400].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([OH:43])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:44]1CCC(N=C=NC2CCCCC2)CC1>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:41]([O:43][CH3:44])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared by treating Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(2-thiophenesulfonyl)-L-phenylalanyl]-L-lysine (60 mg, 0.1 mmol, example 24) dissolved in MeOH (2 mL) with DCC (1 eq.). The reaction mixture was stirred at room temperature for a period of 2 h. Filtration and evaporation of the solvent followed by HPLC purification gave the desired methyl ester (15 mg, 22%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[F:12][C:13]([F:19])([F:18])[C:14](OC)=[O:15].Cl>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]([C:14](=[O:15])[C:13]([F:19])([F:18])[F:12])[CH:3]=[C:4]([F:11])[C:5]=1[O:9][CH3:10]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: COC(=O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(F)cc(C(=O)C(F)(F)F)cc1F
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Isopropyl magnesium chloride lithium chloride complex (22.0 mL, 28.02 mmol) was added dropwise to a stirred solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.0 g, 22.42 mmol) at −5° C. in THF (100 mL) and the reaction mixture was stirred at same temperature for 30 min. Methyl triflouroacetate (3.67 g, 28.69 mmol) was added dropwise and then the reaction mixture was stirred at ambient temperature for 2 h. A 2 N HCl solution (200 mL) was added to quench the reaction and then it was extracted with diethylether. The organic combinded layers were washed with brine dried (Na2SO4), filtered and concentrated to afford the title compound (5.4 g, crude) as a yellow liquid. The material was taken on to next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.68-7.60 (m, 2H), 4.19 (s, 3H); ESIMS m/z 240.1 ([M]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][N:12](C(=O)C)[CH2:13][CH2:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2].[ClH:18]>CCO.O>[ClH:18].[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc2c1CN(C(C)=O)CC2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1noc2c1CNCC2

Procedure:
31.1 g (130 mmol) of 5-acetyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (C) were dissolved in 30 mL of EtOH and combined at RT with 30 mL (260 mmol) of 32% (weight percent) hydrochloric acid solution in water. After two hours' heating with refluxing, the solution was evaporated and introduced into 500 mL of cooled EtOAc (ice bath). The resultant precipitate was separated and dried under a vacuum. 8.13 g (27% of theoretical) of the desired product 4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (D) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([N+]([O-])=O)[CH:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH3:10])[C:6]=2[F:9])[CH:13]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)n1
Product: Cc1ccc(Cl)c(Oc2cc(Cl)nc(C#N)c2)c1F
Yield: 88.2 %

Procedure:
The title compound was prepared in a similar manner to that described herein using 6-chloro-2-fluoro-3-methylphenol (0.60 g, 3.74 mmol) and 6-chloro-4-nitro-2-pyridinecarbonitrile (0.69 g, 3.74 mmol) to give the title compound as a white solid (0.98 g, 88%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.24 (1H, m) 7.16 (1H, d) 7.14 (1H, d) 6.98 (1H, d) 2.33 (3H, d). LCMS: m/z 297 (M+1).
Reaction SMILES: [OH:1][C@H:2]([CH3:39])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][N:14]=2)=[O:11])[C:6](=[O:32])[N:5]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:40]([N:50]([CH2:52][C:53](O)=[O:54])[CH3:51])([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:43]([O:42][C:40]([N:50]([CH3:51])[CH2:52][C:53]([O:1][C@H:2]([CH3:39])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10](=[O:11])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][N:14]=2)[C:6](=[O:32])[N:5]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:54])=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a mixture of (R)-1-(2-hydroxypropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.81 mmol), N-Cbz-sarcosine (1.7 g, 7.62 mmol) and DMAP (0.93 g, 7.62 mmol, Aladdin) in 15 mL of CH2Cl2 at 0° C. was added EDC solid (2.19 g, 11.43 mmol, Aladdin) in portions. After stirring at 0° C. for 2 hrs, the mixture was allowed to heat to 40° C. and stirred overnight. The reaction was diluted with 100 mL of CH2Cl2. The resulted solution was washed with 0.1 N HCl (10 mL×2), saturated NaHCO3 (20 mL×2) and followed by water (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH=4/1) to give the title compound as a yellow solid (2.15 g, 77.3%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:3]=[CH:2][CH2:1][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: C=CCOc1ccc(Br)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Fc1ccc(OC=CCOc2ccccc2)cc1
Yield: 49.1 %

Procedure:
A solution of 4-allyloxybromobenzene (42.24 g, 198.3 mmol), 4-fluorophenol (14.82 g, 132.2 mmol), potassium carbonate (27.41 g, 198.3 mmol) and copper (4.20 g, 66.1 mmol) in pyridine (200 mls) was refluxed for 2 days. It was then filtered through Celite and diluted with ethylacetate(500 mls). The organic was then washed with water (3×200 mls), dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, hexanes:ether, 99.75:0.25) to afford 15.85 g (49%) of 4-(4-fluorophenoxy)allyloxybenzene as a lemon yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[C:8]2[C:4]=1[C:5](=N)[NH:6][C:7]2=[NH:16].[ClH:18].[CH2:19]([CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][CH2:28][C:29](=[NH:31])[N:30]=2)[CH2:22]1)[CH3:20].N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:18].[NH:16]=[C:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:9]=2[O:14][CH3:15])[C:5](=[C:28]2[S:27][C:26]([N:23]3[CH2:24][CH2:25][CH:21]([CH2:19][CH3:20])[CH2:22]3)=[N:30][C:29]2=[NH:31])[NH:6]1
Reactant: COc1cc(OC)c2c(c1OC)C(=N)NC2=N
Reactant: CCC1CCN(C2=NC(=N)CS2)C1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: CCC1CCN(C2=NC(=N)C(=C3NC(=N)c4c(OC)cc(OC)c(OC)c43)S2)C1

Procedure:
When equivalent amounts of 4,5,7-trimethoxy-1,3-diiminoisoindoline and 2-(3-ethypyrrolidino)-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part C above, there is obtained as the product 1-imino-4,5,7-trimethoxy-3-[2-(3-ethylpyrrolidino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19].ClC1C=C([O:29]CCN2CCOCC2)C=CC=1C(=O)CCC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:29][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19]
Reactant: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: CCCC(=O)c1ccc(OCCN2CCOCC2)cc1Cl
Product: C=C(CC)C(=O)c1ccc(OCCN2CCOCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step B except that the 1-[2-chloro-4-(2-diethylaminoethoxy)phenyl]-1-butanone of Example 1, Step B is replaced by an equimolecular quantity of 1-[2-chloro-4-(2-morpholinoethoxy)phenyl]-1-butanone. The product is obtained as a yellow oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][N:40]([CH2:42][CH2:43][OH:44])[CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:38]=[N:39][N:40]([CH2:42][CH2:43][OH:44])[CH:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc(N)c1-c1cnn(CCO)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
The title compound was prepared following the experimental procedure described in Example 3 from 100 mg (0.21 mmol) of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one and 76 mg (0.32 mmol) of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol. After 18 hours heating, an excess of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (76 mg), palladium catalyst (19 mg) and aqueous sodium carbonate solution (317 μl) were added and the reaction mixture was stirred at 80° C. for 24 hours more. The product was purified by flash chromatography (0% to 15%, dichloromethane-methanol) to obtain 46 mg (48% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:49])[C:32]([C:47]#[N:48])=[CH:33][C:34]([N:37]([CH2:45][CH3:46])C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C:34]([NH:37][CH2:45][CH3:46])([CH3:35])[CH3:36])[C:47]#[N:48])=[O:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate (60 mg, 0.089 mmol) in DCM (10 mL) was added 2.5 mL of CF3COOH. The mixture was stirred for 2 h at room temperature. The volatile phase was removed under reduced pressure and the residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted 12 mg (16%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 569 (M+H+). H-NMR (400 MHz, CD3OD, ppm): 8.37 (s, 1H), 7.72 (s, 1H), 7.57 (t, J=8.4 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.17 (d, 8.0 Hz, 2H), 6.97 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.91 (dd, J=11.6 Hz, 2.0 Hz, 1H), 4.95-4.82 (m, 2H), 4.70-4.65 (m, 1H), 3.71-3.65 (m, 3H), 3.59-3.55 (m, 1H), 2.15-2.11 (m, 1H), 2.02-1.93 (m, 2H), 1.81-1.79 (m, 1H), 1.53 (s, 3H), 1.47 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH:19]([CH3:23])[C:20]([NH:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:10])=[O:21]
Reactant: CC(Cl)C(=O)Cl
Reactant: N[C@@H](CO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-phenylglycinol (1.00 g, 7.3 mmol) and triethylamine (1.02 mL, 7.3 mmol) in CH2Cl2 (50 mL) at 0° C. was slowly added 2-chloropropionyl chloride (0.72 mL, 7.3 mmol). After 20 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=228 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:15][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCCCC1
Reactant: CNC
Product: CN(C)CC1(c2cccc(C(F)(F)F)c2)CCCCC1
Yield: 51.9 %

Procedure:
The title compound was prepared from 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give N,N-dimethyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (74 mg, 52%) as a clear oil. 1H NMR (CDCl3): δ 1.29-1.38 (m 3H), 1.48-1.57 (m, 3H), 1.63-1.70 (m, 2H), 1.97 (s, 6H), 2.11-2.15 (m, 2H), 2.34 (s, 2H), 7.41-7.43 (m, 2H), 7.56-7.59 (m, 1H), 7.63 (s, 1H). 13C NMR (CDCl3) δ 22.4, 26.7, 34.3, 43.9, 48.6, 72.7, 122.4, 124.3, 128.6, 126.0, 131.1, 147.6, 150.8.ESI MS m/z 286.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([NH:34][C@H:35]([C:39](O)=[O:40])[C@@H:36]([CH3:38])[OH:37])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:34][C@@H:35]([C@H:36]([OH:37])[CH3:38])[C:39]([N:23]1[CH2:24][CH2:25][CH:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:26])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:40]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](O)[C@H](N)C(=O)N1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1

Procedure:
The preparation was carried out analogously starting from 200 mg (0.47 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 113 mg (0.52 mmol) of N-(tert-butoxycarbonyl)-L-threonine. The protecting group was cleaved off as already described using HCl in dioxane. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.