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: CCCCCC
Solvent: CCOCC
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][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=NCCCC.C(OC(=O)C)(=O)C.[N+:26]([CH2:29][C:30](=[O:32])[CH3:31])([O-:28])=[O:27]>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[C:29]([N+:26]([O-:28])=[O:27])[C:30](=[O:32])[CH3:31]
Reactant: CCCCN=Cc1ccccc1SCCCCCl
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(=Cc1ccccc1SCCCCCl)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 2 liter 4-neck round-bottom flask fitted with mechanical stirrer and thermowell, under a nitrogen atmosphere, was added 138.2 g of N-{2-[(4-chlorobutyl)thio]phenylmethylene}-1-butanamine and 350 ml of benzene, followed by 91.9 ml of acetic anhydride. The mixture was cooled in an ice water bath as 50.18 g of nitroacetone was added. The bath was permitted to warm to room temperature and the reaction stirred overnight. The solvent was removed by rotary evaporation and the product was partitioned between ether and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to dryness. Purification via column chromatograph on silica gel, eluting with 15% ethyl acetate in hexane provided the product as a pale orange oil. Mass spectrum: 314 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>>[CH2:23]([NH:26][C:20]([C@@H:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:22])[CH2:24][CH3:25]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: CCCN
Product: CCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1

Procedure:
The process is performed as in Example 14 a), starting with N-benzyloxycarbonyl-2(S)-indolinecarboxylic acid prepared as in Example 16 a) and n-propylamine. A white solid is obtained, which is recrystallized from CCl4.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (8.00 g) in anhydrous DMF (50 ml) was added dropwise to a suspension of sodium hydride (1.08 g) in anhydrous DMF (200 ml), and the resulting mixture was stirred at room temperature for 80 minutes. To the reaction solution, 2-iodopropane (4.03 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. Sodium hydride (1.08 g) was added to the reaction solution and thereafter 2-iodopropane (4.03 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 6 hours. Water was added to the reaction solution and the resulting mixture was extracted twice with ethyl acetate. Organic layers were washed 4 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane, cyclohexane/ethyl acetate=50/1). The obtained solid was recrystallized from hexane to obtain N-(4-iodophenyl)-N-isopropylpyrimidin-2-amine (7.06 g). NMR (H1, CDCl3): δ 1.14 (3H, s), 1.16 (3H, s), 5.12-5.19 (1H, m), 6.52 (1H, t, J=4.6 Hz), 6.88-6.92 (2H, m), 7.74-7.77 (2H, m), 8.29 (2H, d, J=4.6 Hz)
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.CO>CN1CCCC1=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12]([NH:30][C:29]4[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=4)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8 replacing methyl 2-fluorophenoxyacetate with methyl 4-fluorophenoxyacetate-Step A-B, 0.35 g, 1 mmol) and 4-fluoroaniline (0.284 mL, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the crude product which was purified by column chromatography (SiO2, CH2Cl2/MeOH—95/5). The column fractions were combined and concentrated under reduced pressure to provide the free amine. This was suspended in ethyl acetate (1-2 mL) and hydrochloric acid in ether (1M, 1.2 eq) was added. Isolation of the solid via filtration and drying provided 0.101 g of the hydrochloride salt (Mass spec. M+1=381, MP=242.3-242.6° C.).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:51]([O:55][C:56]([N:58]([CH2:66][C:67]1[CH:68]=[C:69]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH:70]=[CH:71][CH:72]=1)[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C)C=O>[C:62]([O:61][C:59]([N:58]([CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH:73]2[CH2:74][CH2:75][N:76]([C:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:10]=3)=[O:17])[CH2:77][CH2:78]2)[CH:68]=1)[C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:57])=[O:60])([CH3:63])([CH3:64])[CH3:65]
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCNCC2)c1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.25 g, 1.1 mmol) in anhydrous dimethylformamide (5 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.42 g, 1.1 mmol) and diisopropylethylamine (0.5 ml, 3 mmol). This mixture was stirred 15 minutes at ambient temperature and then treated with a solution of 4-{3-[N,N-Bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidine (0.39 g, 1.0 mmol) in dimethylformamide (5 ml). After stirring at ambient temperature for 18 hours the reaction mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (15 ml). The organic layer was dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of dichloromethane and methanol (49:1, v/v) to give N,N-bis-(tert-butoxycarbonyl)-3-[1-(5-phenylethynyl -pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine as a yellow oil (0.25 g). 1H NMR [(CD3)2SO, 500 MHz]: δ 8.82 (s, 1H), 8.62 (s, 1H), 8.02 (s, 1H), 7.61 (m, 2H), 7.45 (m, 3H), 7.30 (m, 1H), 7.20 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 4.68 (s, 2H), 4.62 (br m, 1H), 3.60 (br m, 1H), 3.23 (br m, 1H), 2.85 (m, 2H), 1.83 (br m, 1H), 1.65 (m, 3H), 1.39 (s, 18H). MS(EI): 596(M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:19][C:20]1[CH:25]=[C:24]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:10]3[NH:11][CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH2:14]2)[N:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Clc1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccc(Cl)cc4)c[nH]3)C2)n1
Yield: 46.1 %

Procedure:
A solution of 2-[4-(4-chlorophenyl)-1H-imidazol-2-yl]morpholine (322 mg, 1.22 mmol), 4,6-dichloro-2-pyrimidinamine (200 mg, 1.220 mmol) and Hunig's base (531 μL, 3.05 mmol) in ethanol (6.1 mL) was heated at 85° C. overnight. The mixture was evaporated and chromatographed (PE-EtOAc, 2:3) to afford the title compound (220 mg). LC-MS (ES) m/z=391 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[CH2:22]([OH:25])[CH2:23][OH:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:24][CH2:23][CH2:22][OH:25])[CH:19]=[CH:18][N:17]=1
Reactant: OCCO
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (1 g, 2.45 mmol), ethane-1,2-diol (15 mL) and cesium carbonate (3 g, 9.18 mmol) was stirred overnight at room temperature and then diluted with 200 mL of water. The resulting solution was extracted with 2×200 mL of dichloromethane. The combined organic layers were washed with 3×200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 300 mg (34%) of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol as a yellow solid. 1H NMR (300 MHz, DMSO) delta 8.39 (d, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.51 (s, 2H), 7.09 (d, J=5.4 Hz, 1H), 4.78 (t, J=5.2 Hz, 2H), 4.08 (t, J=4.2 Hz, 2H); LC-MS: m/z=+350 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([NH2:25])=[S:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CC(C)=O>[C:13]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]2[S:24][CH:2]3[CH2:10][C:9]4[CH:8]=[C:7]([Cl:11])[CH:6]=[CH:5][C:4]=4[C:3]3([OH:12])[N:25]=2)=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccc(OCC(N)=S)cc1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(OCC2=NC3(O)c4ccc(Cl)cc4CC3S2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At room temperature, 0.49 g of 2-bromo-5-chlorindan-1-on and 0.45 g of 2-(4-tert-butylphenoxy)-thioacetamide were dissolved in 10 ml of dry acetone, and the mixture was stirred at room temperature for 12 h. The precipitated hydrobromide was filtered off with suction and washed with acetone. The residue was suspended in a little ethyl acetate and treated with saturated sodium bicarbonate solution. The organic phase was separated off, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This synthesis yielded 2-(4-tert-butylphenoxymethyl)-6-chloro-8,8a-dihydroindeno [1,2-d]thiazol-3a-ol having a melting point of 122-124° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([CH2:14][N:15]=[N+:16]=[N-:17])(O)[CH2:10][C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:36])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][N:15]=[N+:16]=[N-:17])([F:36])[CH2:10][C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@](F)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2S,4S)-4-azidomethyl-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (430 mg, 1.0 mmol) in CH2Cl2 (25 mL) under N2 atmosphere at −78° C. was added DAST (266 μL, 2.01 mmol). The reaction mixture was allowed to warm up to RT and further stirred for 1.5 h. The reaction mixture was poured into an aqueous saturated solution of NaHCO3 and extracted twice with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) to give the desired material. MS (LC/MS): 474.1/476.2 [M+H]+, 472.1 [M−H]−; tR (HPLC conditions f): 2.23 min, 19F NMR (100 MHz, DMSO-d6) δ (ppm): −120, −150.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Sc2ccccc2)c1
Product: c1ccc(Sc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 71A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound as a clear oil. (1.06 g, 46%).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:45][O:46]C1C=CC=C(OC)C=1CN>>[Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[C:32]([O:46][CH3:45])=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Reactant: COc1cccc(OC)c1CN
Product: COc1cccc(OC)c1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1

Procedure:
Prepared analogously to 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide using 2,6-dimethoxybenzylamine to give the title compound as a pale yellow foam.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH2:12]([O:14][CH2:15][C:16]([OH:18])=O)[CH3:13].Br.[NH2:20][C:21]1[S:22][C:23]([Br:26])=[CH:24][N:25]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:26][C:23]1[S:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][O:14][CH2:12][CH3:13])=[N:25][CH:24]=1
Reactant: Nc1ncc(Br)s1
Reactant: CCOCC(=O)O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCC(=O)Nc1ncc(Br)s1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
EDCI (0.53 g, 2.78 mmol) was added to a solution of ethoxyacetic acid (0.29 g, 2.78 mmol) in CH2Cl2 (5 ml) under ice-cooling. After stirring for 1 h, a solution of 2-amino-5-bromothiazole hydrobromide (0.60 g, 2.31 mmol) and diisopropylethylamine (0.40 ml, 2.34 mmol) in CH2Cl2 (5 ml) was added dropwise, and the entire mixture was kept at 0° C. for 1 h, then at room temperature overnight. The solution was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was further washed with water, 5% citric acid, water, saturated sodium bicarbonate, and water. Drying over sodium sulfate and evaporation gave a solid which was triturated with isopropyl ether to give the title compound as a beige solid (0.43 g; 70%)
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([NH:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:10])=[O:6])[CH3:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Agent: Br
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
2 g (0.00585 mol) of L-alanyl-L-proline anilide hydrobromide were dissolved in 40 ml of dry pyridine and 1.1 ml (0.0117 mol) of acetic anhydride were added. The solution was stirred at room temperature for 1 hour and then evaporated. Final traces of pyridine were removed by addition of 20 ml of toluene ane re-evaporation. The residue was dissolved in 100 ml of chloroform and the solution washed with 80 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to an oil. This oil crystallised from ethyl acetate/petroleum ether to give 1.64 g (93%) of N-acetyl-L-alanyl-L-proline anilide of melting point 163°-165° C.; [α]D20 =-186.2° (c=1.022% in methanol).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][C:19]=1[NH:27][C:28](=[O:31])[NH:29][NH2:30])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][C:19]=1[NH:27][C:28](=[O:31])[NH:29][N:30]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8])[CH3:16]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CCOc1ccc(OCC)c(NC(=O)NN)c1
Agent: Cl
Product: CCOc1ccc(OCC)c(NC(=O)NN=c2c(=O)c3ccccc3c2=O)c1

Procedure:
ninhydrin, 4-(2,5-diethoxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C.CCOC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Clc1ncccn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2ncccn2)CC1

Procedure:
As shown in step 5-i of Scheme 5, a mixture of tert-butyl ((cis)-4-aminocyclohexyl)carbamate (compound 1009, 490 mg, 2.3 mmol), 2-chloropyrimidine (262 mg, 2.3 mmol) and TEA (463 mg, 637θL, 4.6 mmol) in DMF (10 mL) was subjected to microwave irradiation for 20 minutes at 150° C. The reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 50% EtOAc/hexanes gradient) to provide tert-butyl ((cis)-4-(pyrimidin-2-ylamino)cyclohexyl)carbamate (compound 1010) as a white solid: 1H-NMR (300 MHz, CDCl3) δ 8.28 (d, J=4.8 Hz, 2H), 6.53 (t, J=4.8 Hz, 1H), 5.12 (s, 1H), 4.56 (s, 1H), 3.99 (dq, J=7.0, 3.5 Hz, 1H), 3.65 (s, 1H), 1.83 (tq, J=10.2, 3.6 Hz, 5H), 1.66 (s, 8H), 8.13-7.91 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]([O:24]CC)=O)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([NH2:29])=O.C[O-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]([NH2:29])=[O:24])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: NC=O
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)o1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(C(N)=O)oc2-c2ccc(OC)cc2)cc1
Yield: 71.9 %

Procedure:
In WO2004/065374 is disclosed a method in which ethyl 4,5-bis(4-methoxyphenyl)-1,3-oxazole-2-carboxylate, which is a carboxylic acid ester, is allowed to react with formamide in the presence of sodium methoxide, which is a metal alkoxide, to give 4,5-bis(4-methoxyphenyl)-1,3-oxazole-2-carboxamide, which is a carboxamide, in a yield of 71.9% (see Example 2).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([SiH2:10][O:11][C:12]([CH3:29])([CH3:28])[C:13]1[C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[C:17]=2[CH:16]=[CH:15][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.[CH:38](N1CCCCC1)=[O:39].Cl>C(OCC)C>[C:6]([SiH2:10][O:11][C:12]([CH3:29])([CH3:28])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:26]=1[S:25][C:24]1[C:23]([CH2:38][OH:39])=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]2[CH3:27])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=CN1CCCCC1
Reactant: CN1c2ccccc2Sc2c1cccc2C(C)(C)O[SiH2]C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CN1c2cccc(CO)c2Sc2c1cccc2C(C)(C)O[SiH2]C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
36.4 ml of tert-butyllithium solution (1.4M in pentane) were slowly added dropwise under argon at -78° to a solution of 14.0 g (39.2 mmol) of 4-(tert-butyl-dimethyl-silanyloxymethyl)-10-methyl-phenothiazine and 6.39 ml of N,N,N',N'-tetramethylethylenediamine in 120 ml of diethyl ether. The reaction mixture was stirred at -78° for 30 minutes, brought slowly to room temperature, stirred for 3 hours, thereupon treated with 5.66 ml (51.0 mmol) of N-formylpiperidine, stirred at 0° for 40 minutes and then poured into 50 g of ice, 50 ml of 0.1N aqueous hydrochloric acid solution and 250 ml of diethyl ether. The aqueous phase was extracted several times with diethyl ether. The combined organic phases were dried over magnesium sulphate and concentrated. The crude 6-(tert-butyl-dimethyl-silanyloxymethyl)-10-methyl-phenothiazine-4-carbaldehyde (about 14 g) remaining as the residue was dried in a high vacuum, dissolved in 120 ml of tetrahydrofuran and treated at 0° with 50 ml of lithium borohydride solution (1N in tetrahydrofuran). The reaction mixture was stirred at room temperature for 1 hour and then poured into 100 ml of 0.1N aqueous hydrochloric acid solution, 100 g of ice and 150 ml of diethyl ether. The aqueous phase was extracted with diethyl ether and the combined organic fractions were dried over magnesium sulphate and concentrated. The residue was chromatographed on 1.3 kg of silica gel with ethyl acetate/hexane (1:4), whereupon, after drying in a high vacuum, 4.57 g (30.0%) of [6-(tert-butyl-dimethyl-silanyloxymethyl)-10-methyl-phenothiazin-4-yl]-methanol were obtained as a colourless oil. MS: 387 (M+ ; 100), 238(91), 224(24), 75(97).