Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[N:20]=[C:19]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)(C)(C)C.ClC1N=C(N(C2C=CC(OC)=C(OC)C=2)C)C2C(=CC=CC=2)N=1.C(N(C(C)C)C(C)C)C.C(OC(=O)NCCN)(C)(C)C>CCCCO>[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:20]=[C:19]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(N(C)c2nc(NCCNC(=O)OC(C)(C)C)nc3ccccc23)cc1OC
Agent: CC(C)(C)OC(=O)NCCN
Agent: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCN)nc3ccccc23)cc1OC
Yield: 91 %

Procedure:
(2-{4-[(3,4-Dimethoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester: A soln of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine (440 mg, 1.33 mmol), ethyl-diisopropyl-amine (0.47 mL, 2.70 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (316 μL, 2.00 mmol) in n-BuOH (5 mL) was reacted at 110° C. for 29 h then concd on a rotary evaporator. The crude material was dissolved in CHCl3 (8 mL) then washed with satd NaHCO3 (2×3 mL) and water (1×3 mL). This soln was dried (MgSO4), filtered through a plug of silica with a wash of 100:10:1 CHCl3:MeOH:concd NH4OH, concentrated, then purified by MPLC (amine column (Isco 68-2203-101)/0-100% i-PrOH in CHCl3.), yielding the title compound as a tan solid (550 mg; 91%). 1H NMR (CDCl3) δ 7.46-7.35 (m, 2H), 6.90-6.82 (m, 2H), 6.77-6.66 (m, 3H), 5.80 (s(br), 1H), 5.44 (s(br), 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.68 (m, 2H), 3.53 (s, 3H), 3.44 (m, 2H), 1.44 (s, 9H); LC-MS (ESI+; 454 ([M+H]+)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1c[nH]c2ccccc12)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 43 %

Procedure:
The title compound is prepared from 1H-indole-3-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 43% of theory; LC (method 4): tR=2.01 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br>C(Cl)(Cl)Cl.C(OCC)C>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1ccccc1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2′-Methylacetophenone (16.0 g) was dissolved in chloroform (50 mL) and diethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform (15 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) as an oil. To a solution (700 mL) of methyl cyanoacetate (10.9 g) and diisopropylethylamine (31.0 g) in tetrahydrofuran was added dropwise a solution (100 mL) of crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) obtained above in tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 hr, then at 70° C. for 2 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-cyano-4-(2-methylphenyl)-4-oxobutanoate as an oil (yield 16.0 g). This was dissolved in ethyl acetate (16 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (80 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-chloro-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate as an oil (yield 2.7 g). This was dissolved in methanol (15 mL), 10% palladium carbon (50% containing water, 1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 0.66 g, 3%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][O:15][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C1=C(COCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
1.016 g (0.0050 mol) of (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol were added to a suspension of 0.20 g (0.0050 mol) of NaH (60% in oil) in 10 ml of tetrahydrofuran and the mixture was stirred at room temperature for 30 minutes Then, 0.60 ml (0.0050 mol) of benzyl bromide was added and the mixture was stirred at room temperature for a further 2 hours. The reaction mixture was subsequently treated with water and extracted with diethyl ether. The organic phase was dried over MgSO4, concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate 9:1 to 3:1 as the eluent. 0.515 g (35%) of 1-benzyl-4-benzyloxymethyl-1,2,3,6-tetrahydropyridine was obtained as a yellow oil. MS (ISP): me/e=2.94 (C20H24NO+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>C(O)C.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:19][O:18][N:20]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CON
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 99.4 %

Procedure:
A solution of 4,4′-difluorobenzophenone (3.00 g, 13.75 mmol) in a mixture of ethanol (10 ml) and pyridine (10 ml) was treated with methoxylamine hydrochloride (1.8 g, 21.7 mmol) and the resulting mixture was heated under reflux for 1 h. The cooled reaction mixture was diluted with ethyl acetate, washed successively with water, 1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulphate, evaporation of the solvent yielded 3.38 g (99% yield) of the title oxime ether as a clear syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.94 (3H, s, OCH3), 7.04 (2H, m, aromatics), 7.12 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.45 (2H, m, aromatics).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][CH2:24][CH2:25][C:26]1[S:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:30]=1)=[N+]=[N-]>C1COCC1.O>[C:31]1([C:29]2[N:30]=[C:26]([CH2:25][CH2:24][CH2:23][NH2:20])[S:27][CH:28]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: [N-]=[N+]=NCCCc1nc(-c2ccccc2)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCCc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
Triphenylphosphine (485 mg, 1.85 mmol) was added to a solution of 2-(3-azidopropyl)-4-phenylthiazole (0.3 g, 1.23 mmol) in THF—H2O (10 mL, 8:2 v/v) at 0° C. The reaction mixture was allowed to warm up to room temperature, stirred for 8 h and then concentrated under reduced pressure. The residue was diluted with 1.5N HCl and the aqueous layer was washed with CH2Cl2. The pH of the aqueous layer was adjusted to ˜8-9 using 10% NaOH solution and the organic product was extracted with CH2Cl2. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 3-(4-phenylthiazol-2-yl)propan-1-amine (240 mg, yield 89%) as a pale yellow liquid, which was carried through without further purification. MS (ESI) m/z: Calculated for C12H14N2S: 218.09. found: 219.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH:6]([F:8])[F:7])[CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25].CO>ClCCl.CC(OC)(C)C>[Br:15][C:11]1[CH:10]=[C:9]([C:3]([NH:2][C:24](=[O:25])[CH2:23][Cl:22])([CH2:4][OH:5])[CH:6]([F:7])[F:8])[CH:14]=[CH:13][CH:12]=1
Reactant: NC(CO)(c1cccc(Br)c1)C(F)F
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: COC(C)(C)C
Product: O=C(CCl)NC(CO)(c1cccc(Br)c1)C(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Amino-2-(3-bromo-phenyl)-3,3-difluoro-propan-1-ol hydrochloride (6.5 g, 24.43 mmol) was put between 60 ml aqueous 2 M Na2CO3 solution and 60 ml dichloromethane and cooled to 0° C. under strong stirring. Then chloroacetylchloride (2.94 ml, 36.6 mmol), diluted in 8 ml dichloromethane, was added dropwise to the biphasic solution. After the complete addition, the reaction was stirred for 30 minutes at r.t. After completion 10 ml MeOH were added and stirring was continued for 10 minutes. Then TBME und water were added. The phases were separated, and the aqueous phase was extracted with TBME. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 8.72 (s, 1H), 7.53 (m, 2H), 7.35 (m, 2H), 6.48 (t, 1H, CHF2), 5.39 (t, 1H), 4.18 (m, 2H), 3.10 (s, 2H); MS: 342 [(M+H)+].
Reaction SMILES: O1CCCC1.[F:6][C:7]1[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)=[N:9][CH:10]=[CH:11][CH:12]=1.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ncccc2F)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ncccc4F)cc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 92 %

Procedure:
To a tetrahydrofuran (2 mL) solution of (4-(3-fluoro-pyridin-2-yloxymethyl)-phenyl)acetohydroximoyl chloride (33 mg, 0.11 mmol) described in Manufacturing Example 149-1-4 were added 3-ethynyl-pyridin-2,6-diamine (10 mg, 75 μmol) described in Manufacturing Example 13-1-3 and triethylamine (21 μL, 0.15 mmol), which was stirred for 2 hours and 25 minutes at 50° C. and under nitrogen atmosphere. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (27 mg, 92%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:26]2[CH:27]=[C:28]([O:36][CH3:37])[C:29]3OCOC[C:30]=3[CH:35]=2)[C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[N:19]=[CH:20][S:21][C:22]=3[C:23]([OH:25])=[O:24])[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH3:38][O:39]C(=O)N=C(SC)C(C1C=C(OC)C=C(OC)C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:26]2[CH:27]=[C:28]([O:36][CH3:37])[CH:29]=[C:30]([O:39][CH3:38])[CH:35]=2)[C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[N:19]=[CH:20][S:21][C:22]=3[C:23]([OH:25])=[O:24])[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)cc2c1OCOC2
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OC)c1
Product: COc1cc(OC)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (166a) to (166c), except that {2-(3,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (225a)) was used instead of [2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (166a), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].[CH2:15](O)[CH3:16]>OS(O)(=O)=O>[CH2:15]([O:12][C:11]([C:9]1[CH:8]=[C:7]([CH3:14])[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)=[O:13])[CH3:16]
Reactant: Cc1cc(C(=O)O)nc(NC(C)C)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)nc(NC(C)C)n1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid (1.27 g, 6.53 mmol) in ethanol (20 mL), concentrated H2SO4 (4 mL) is added. The reaction mixture is stirred at 80° C. for 18 h and is then evaporated. The residue is dissolved in EtOAc, washed with sat. aq. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The crude compound is purified by CC on silica gel (eluting with Heptane/EtOAc 4:1) to give 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid ethyl ester as a yellow oil (1.46 g); LC-MS: tR=0.97; [M+H]+=224.49.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[C-:19]#[N:20].[K+]>C(OCC)C>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([OH:8])([C:19]#[N:20])[CH2:4][CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: [C-]#N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC1CCC(O)(C#N)CC1

Procedure:
4-Methylcyclohexanone (1.0 g, 8.9 mmol) was added to a stirred solution of water (8.9 mL) containing sodium metabisulfite (0.98 g, 5.2 mmol). The resulting mixture was allowed to stir at ambient temperature for 15-30 minutes before diethyl ether (8.9 mL) was added followed by potassium cyanide (0.91 g, 14 mmol). The biphasic mixture was stirred vigorously for at least 30 minutes before the layers were partitioned and the organic layer was washed with water, followed by brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford 4-methyl-1-hydroxycyclohexanecarbonitrile as a crude residue, which was carried forward without further purification. The crude residue (0.50 g, 3.6 mmol) was combined with pyridine (18.3 mL, 226 mmol), and POCl3 (1.34 mL, 14.4 mmol) in a microwave vial and sealed. The reaction mixture was heated to reflux for 16 hours. The reaction mixture was then cooled to ambient temperature, diluted with diethyl ether, and washed with 2N aqueous HCl saturated with sodium chloride (3×). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo (23° C. water bath) to afford the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][CH2:20][C:21](=O)[CH3:22])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]2[S:33][C:21]([CH3:22])=[CH:20][N:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Product: Cc1cnc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)s1

Procedure:
The title compound was prepared by a similar method to Example 29 from (2S)-1-[(4-fluorophenyl)sulfonyl]-N2-(2-oxopropyl)-2-piperidinecarboxamide [see Preparation 81] and Lawesson's reagent. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 75:25, by volume, hexane:ethyl acetate, in 5% increments, to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(5-methyl-1,3-thiazol-2-yl)piperidine as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=1>>[O:15]1[CH2:16][CH2:17][N:12]([CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([N:19]3[C:20](=[O:24])[CH:21]=[CH:22][CH:23]=[N:18]3)=[CH:3][CH:4]=2)[CH2:13][CH2:14]1
Reactant: Brc1ccc([C@H]2C[C@@H]2CN2CCOCC2)cc1
Reactant: O=c1cccn[nH]1
Product: O=c1cccnn1-c1ccc([C@H]2C[C@@H]2CN2CCOCC2)cc1

Procedure:
Following the general procedure, reaction of 7e (2.59 g assayed, 8.75 mmol) with 3(2H)-pyridazinone (1.09 g, 11.37 mmol) afforded a solution of the free base of 8e in an assayed yield of 2.03 g (50% assay yield, 96% peak area).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21])[C:30](=[O:31])[C:29]1[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) and using a gradient of n-heptane:EtOAc (100:0 to 0:80) for the chromatographic purification. Colorless solid (30%). MS (ESI): m/z=559.096 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][Br:21]
Reactant: Cc1cccc(C(F)(F)C(F)(F)c2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(CBr)cccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 4.0 g. (0.0142 mole) of 2,3-dimethyl-α,α,α',α'-tetrafluorobibenzyl, 2.52 g. (0.0142 mole) of N-bromosuccinimide, about 50 mg. of benzoyl peroxide, and 100 ml. of carbon tetrachloride is stirred at reflux for 21/2 hours. After cooling, the precipitate of succinimide is removed by filtration and the filtrate is evaporated to dryness under reduced pressure. The residual solid is recrystallized from petroleum ether to yield the white crystalline product, m.p. 67°-71°C. Repeated recrystallization from petroleum ether affords the analytical sample, m.p. 69°-71°C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>N1C=CC=CC=1>[OH:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:16][CH2:17]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: c1ccncc1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (235 mg) in pyridine (1.5 mL) was added trans-4-aminocyclohexanol (292 mg), and the mixture was stirred for 3 hours at 80° C. After evaporation of the solvent, the residue was dissolved in water and neutralized with 1N-hydrochloric acid (1.9 mL). The resulting precipitates were collected by filtration and washed successively with water and methanol to give 2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (279 mg) as a solid substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15].C(N(CC)CC)C>C(Cl)Cl>[F:12][C:13]([F:17])([F:16])[CH2:14][NH:15][C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:10]
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Reactant: NCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
2,4-Dichloropyrimidine-5-carbonyl chloride (1 g, 5 mmol) was dissolved in CH2Cl2 (20 mL), 2,2,2-trifluoroethylamine (515 mg, 5 mmol) and triethylamine (1.31 mL, 9 mmol) were added. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was purified by flash chromatography to yield a white solid (780 mg, 60%). MS: m/z=271.9 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:23].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(O)(=O)C>[NH:23]1[C:3]2[C:2](=[C:7]([C:8]3[N:9]=[C:10]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:11]4[S:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:6]=[CH:5][CH:4]=2)[CH:1]=[N:24]1
Reactant: Cc1c(N)cccc1-c1nc(N2CCOCC2)c2sccc2n1
Reactant: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: c1cc(-c2nc(N3CCOCC3)c3sccc3n2)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Reaction of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine under Suzuki conditions yielded 2-methyl-3-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine. To a solution of 2-methyl-3-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine (80 mg) in chloroform (8 mL) and acetic acid (4 mL) was added isoamyl nitrite (36 μL). The reaction mixture was stirred for 1 day at room temperature. The mixture was then quenched with sodium bicarbonate solution and extracted in to chloroform and reduced in vacuo. The residue was purified using flash chromatography to yield 270. MS: ESI MH+ 338