Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][C:32]1[S:36][CH:35]=[N:34][C:33]=1[C:37]([NH:39][NH2:40])=O>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:33]3[N:34]=[CH:35][S:36][C:32]=3[CH3:31])=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: Cc1scnc1C(=O)NN
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1scnc1-c1nnc2n1CCN(C(=O)c1ccc(Cl)c(F)c1Cl)C2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(250 mg, 0.859 mmol) in dry dichloromethane (DCM) (2147 μl) was stirred at room temperature under an atmosphere of argon. Triethyloxonium tetrafluoroborate (179 mg, 0.945 mmol) was added to the stirred solution and the solution was stirred for 2 hours. 5-methyl-1,3-thiazole-4-carbohydrazide (I123) (162 mg, 1.031 mmol) was then added and the resulting solution was stirred for 65 hours (over the weekend), during which time the solvent evaporated. The residue was redissolved in 1-butanol (2147 p1) and the resulting mixture was heated to 110° C. for 3 hours. The solution was allowed to cool to room temperature before being concentrated under reduced pressure to give a yellow coloured oil. The oil was redissolved in DCM (approx. 30 ml) and the organics were subsequently washed with NaHCO3 (sat. aqueous solution approx. 20 ml) and brine (approx. 20 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oil. The oil was chromatographed [SiO2, 0-10% MeOH in DCM] to give a pale yellow coloured oil. The oil was subsequently further purified using MDAP (formic acid method) to give a white coloured solid of desired material in 68 mg.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.OC[NH:68][C:69](=[NH:71])[CH3:70]>CN(C=O)C.O>[CH3:70][C:69]1[N:71]=[C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[O:21][N:68]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(=N)NCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)n1
Temperature: 140 °C
Yield: 69.1 %

Procedure:
To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol), N-ethyldiisopropylamine (1.04 g, 2.0 mmol) and 1-hydroxybenzotriazole hydrate (40 mg, 0.3 mmol) in DMF (16 mL) at ambient temperature and under argon was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (517 mg, 1.6 mmol) followed by N-hydroxymethylacetamidine (149 mg, 2.0 mmol). After 14 h the mixture was diluted with water (15 mL) and extracted with EtOAc (3×25 mL). The combined extracts were washed with 10% aqueous LiCl solution (2×10 mL) then dried over sodium sulfate, filtered and concentrated. The residue was then dissolved in DMF (16 mL) and heated at 140° C. for 3 h then cooled, diluted with EtOAc (60 mL), washed with 10% aqueous LiCl (3×100 mL), then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate 8:2 to 0:1) afforded the title compound (385 mg, 69%) as a yellow solid. MS: m/e=349.4 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][OH:7])[NH:4][C:3]1=[O:8].C(=O)([O-])O.[Na+].Cl.[Cl:15][CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23](/[C:25](=[N:29]/[O:30][CH3:31])/[C:26](Cl)=[O:27])[N:24]=1)=[O:18]>O1CCCC1.O>[Cl:15][CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25](=[N:29][O:30][CH3:31])[C:26]([NH:1][C@H:2]2[C@@H:5]([CH2:6][OH:7])[NH:4][C:3]2=[O:8])=[O:27])[N:24]=1)=[O:18]
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: N[C@@H]1C(=O)N[C@@H]1CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CO)c1csc(NC(=O)CCl)n1

Procedure:
In a mixture of 2 ml of tetrahydrofuran and 2 ml of water is dissolved 75 mg of cis-3-amino-4-hydroxymethyl-2-oxoazetidine as obtained in Reference Example 53C and, under ice-cooling and stirring 168 mg of sodium hydrogen carbonate and then 332 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride are added. The mixture is stirred under ice-cooling for one hour and the reaction mixture is made neutral with aqueous sodium hydrogen carbonate and extracted with ethyl acetate-tetrahydrofuran (2:1). The extract is washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and, after addition of ethyl acetate-ether (1:2), the crystalline residue is recovered by filtration to give cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-hydroxymethyl-2-oxoazetidine (syn-isomer) as colorless crystals, m.p. 238°-241° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].Cl.[OH:26][C:27]1[CH:31]=[C:30]([C:32]([OH:34])=O)[O:29][N:28]=1.[CH3:35][CH2:36]N=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O1CCOCC1.CN(C=O)C.C(O)CCC>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][C@H:7]([NH:21][C:32]([C:30]1[O:29][N:28]=[C:27]([OH:26])[CH:31]=1)=[O:34])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:35][CH3:36]
Reactant: CCOC(=O)C(C)(C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(O)no1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCCCOC(=O)C(C)(C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(O)no1
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(R)-4-Amino-5-biphenyl-4-yl-2,2-dimethyl-pentanoic acid ethyl ester (72.1 mg, 221 μmol, 1.0 eq.) was combined with dry butyl alcohol (5 mL) and 4N HCl in dioxane (1 mL) and stirred at 60° C. overnight. The solvent where evaporated and azeotroped with toluene. To this was added a mixture of 3-Hydroxyisoxazole-5-carboxylic acid (28.6 mg, 221 μmol, 1.0 eq.), EDCI (39.2 μL, 1.0 eq.) and HOBt (29.9 mg, 221 μmol, 1.0 eq.) that had been combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. The resulting mixture was stirred for 30 minutes. The reaction was quenched with AcOH and the product was purified by preparative HPLC and lyophilized to yield the title compound (40 mg, 95% purity). MS m/z [M+H]+ calc'd for C27H32N2O5, 465.23; found 465.4.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[Cl:34][C:35]1[S:39][C:38]([C:40]2[N:44]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:43](=[O:53])[N:42]([CH2:54][C:55]([OH:57])=O)[N:41]=2)=[CH:37][CH:36]=1.C(N(CC)C(C)C)(C)C.O[N:68]=[C:69]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[C:77]([F:80])([F:79])[F:78])[NH2:70]>CN(C=O)C.O>[Cl:34][C:35]1[S:39][C:38]([C:40]2[N:44]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:43](=[O:53])[N:42]([CH2:54][C:55]3[O:57][N:70]=[C:69]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=4[C:77]([F:78])([F:79])[F:80])[N:68]=3)[N:41]=2)=[CH:37][CH:36]=1
Reactant: NC(=NO)c1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(Cc2nc(-c3ccccc3C(F)(F)F)no2)nc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Reaction time: 0.33 h

Procedure:
Under argon, 95 mg (0.18 mmol) of benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate were added to a solution of 56 mg (0.15 mmol) of [3-(5-chloro-2-thienyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [preparation according to WO 2007/134862 Example 154A] and 32 μl (0.18 mmol) of N,N-diisopropylethylamine in 1.5 ml of dry DMF. After 20 min of stirring, 34 mg (0.17 mmol) of N′-hydroxy-2-(trifluoromethyl)benzene-carboximidamide were added. The mixture was then stirred at RT for 16 h. For work-up, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were washed with in each case 10 ml of water and saturated sodium chloride solution, filtered through Extrelut and concentrated under reduced pressure. The residue was dissolved in 2 ml of DMF and stirred in a microwave oven at 250° C. for 15 min. After cooling, the solvent was removed under reduced pressure on a rotary evaporator and the crude product was chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gave 60 mg (72% of theory) of the target compound as a yellow resin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]2[NH:19][CH2:18][C@@H:17]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:16]3[C:15]=2[CH:14]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]2[NH:19][CH2:18][C@@H:17]3[CH2:25][NH:26][CH2:27][C@@H:16]3[C:15]=2[CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COc1cc(Br)cc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Product: COc1cc(-c2ccc(Cl)cc2Cl)cc2c1NC[C@@H]1CNC[C@H]21

Procedure:
Following the procedures described in Example 12, except that 2,4-dichlorophenylboronic acid was used instead of phenylboronic acid, (±)-cis-tert-butyl 8-bromo-6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 11, Part A was converted into the title compound of Example 15. 1H NMR (CDCl3): δ 7.48 (s, 1H), 7.34-7.25 (m, 2H), 6.76 (s, 1H), 6.74 (s, 1H), 4.55 (broad s, 1H), 3.87 (s, 3H), 3.65-3.57 (m, 1H), 3.50-3.25 (overlapping m, 4H), 3.13-2.97 (m, 2H), 2.75-2.65 (m, 1H). LRMS (ES)+: 349.3/351.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH2:19]([N:25]=[C:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCOCC1.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:26]([NH:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCCN=C=O
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: C1COCCO1
Solvent: CN1CCN(C)C1=O
Product: CCCCCCNC(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 160 μl (1.1 mmol) of n-hexyl isocyanate are added and the reaction mixture is stirred overnight at RT. The dioxane is then evaporated off in a rotary evaporator and 30 ml of DIPE and 40 ml of hexane are added to the residue. Filtration with suction and washing with DIPE/hexane yield 4-(3chloro-phenylamino)-3-[(n-hexyl-amino)-carbonyl-amino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100)=10.3; FAB-MS: (M+H)+=388.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cccc(Br)n1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
(6-Bromo-pyridin-2-yl)-methanol (2949 mg, 15.68 mmol), phthalimide (3000 mg, 20.39 mmol), triphenylphosphine (5348 mg, 20.39 mmol) and 1,1-(azodicarbonyl)-dipiperidine) 5144, 20.39 mmol) were dissolved in THF (150 mL) and stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and the resulting precipitate was removed via filtration. A saturated aqueous sodium bicarbonate solution was added to the filtrate and the solution was extracted several times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and condensed under reduced pressure. The crude residue was purified by column chromatography with a gradient of 10 to 75% AcOEt/hexanes to give 2-(6-Bromo-pyridin-2-ylmethyl)-isoindole-1,3-dione as a white solid (4000 mg, 80%) MS ES (MH+ 317.2/319.1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>CN(C=O)C>[CH:25]1([S:28]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[N:11]4[C:12]5[CH:18]=[CH:17][NH:16][C:13]=5[N:14]=[CH:15][C:10]4=[N:9][N:8]=3)[CH2:5][CH2:6]2)(=[O:30])=[O:29])[CH2:27][CH2:26]1
Reactant: c1cc2c(ncc3nnc(C4CCNCC4)n32)[nH]1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=S(=O)(C1CC1)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Reaction time: 3 h
Yield: 6.2 %

Procedure:
To a suspension of 1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.090 g, 0.37 mmol, Example #2) and pyridine (0.12 mL, 1.5 mmol) in DMF (5 mL) was added cyclopropanesulfonyl chloride (0.060 g, 0.41 mmol). After about 3 h at ambient temperature, the reaction mixture was quenched with MeOH (0.5 mL) and then purified by RP-HPLC (Table 2, Method b). The appropriate fractions were concentrated and lyophilized to afford 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazine as a white solid (0.008 g, 6%): LC/MS (Table 2, Method a) Rt=1.52 min; MS m/z: 347 (M+H)+.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[C:25]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:23]=[C:22]([F:44])[N:21]=1.C(O)C>O1CCCC1>[F:19][C:20]1[C:25]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:23]=[C:22]([F:44])[N:21]=1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(F)nc3F)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(F)nc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Lithium hydroxide (0.106 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.24 g) and diethyl [(3S,8aR)-3-(2,6-difluoropyridin-3-yl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.0 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.42 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]([C:8]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:9]=1[CH2:10]O)([CH3:7])[CH3:6].C(O)C>C(OCC)C>[CH:5]([C:8]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:9]=1[CH2:10][Br:2])([CH3:7])[CH3:6]
Reactant: CC(C)c1cc(C(C)C)c(CO)c(C(C)C)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: CCO
Product: CC(C)c1cc(C(C)C)c(CBr)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of phosphorus tribromide (3.8 mL, 0.04 mol) in ethyl ether (150 mL) was added dropwise to 2,4,6-triisopropylbenzyl alcohol (17.99 g, 0.076 mol) in ethyl ether (350 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. Ethanol (95%, 50 mL) was added dropwise over 1 hour and the resulting mixture was stirred for 30 minutes, and was then concentrated to an oil. The oil was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate. The organic layer was washed with water (50 mL), dried (magnesium sulfate), filtered, and concentrated to a clear liquid (22.56 g, 98.9%). This was used directly in the next step.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1.[CH3:34][C:35]1[S:39][CH:38]=[N:37][CH:36]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:34][C:35]1[S:39][CH:38]=[N+:37]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)[CH:36]=1
Reactant: Cc1cncs1
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CBr)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2C[n+]2csc(C)c2)c1
Product: [Br-]
Yield: 98.5 %

Procedure:
A mixture of 2.3 g of N-[2-(bromomethyl)phenyl]-3-(tetradecyloxy)benzeneacetamide and 2.21 g of 5-methylthiazole in 40 ml of toluene is refluxed for 2.5 hours under argon. The solvent is evaporated to a residue which is mixed with ether and the resulting solid collected by centrifugation, washed with ether then dried to give 2.7 g of the desired product as a white powder, m.p. 94°-100° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:15]([O:20][CH2:21][CH2:22][O:23][C:24](=[O:27])[CH:25]=[CH2:26])(=[O:19])[C:16]([CH3:18])=[CH2:17].N[SiH3]>C(#N)C>[C:15]([O:20][CH2:21][CH2:22][O:23][C:24]([CH2:25][CH2:26][N:1]([CH2:26][CH2:25][C:24]([O:23][CH2:22][CH2:21][O:20][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:27])[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[O:27])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=CC(=O)OCCOC(=O)C(=C)C
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: N[SiH3]
Solvent: CC#N
Product: C=C(C)C(=O)OCCOC(=O)CCN(CCC[Si](OCC)(OCC)OCC)CCC(=O)OCCOC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
43 g (0.25 mol) 3-aminopropyl triethoxysilane in 40 ml anhydrous acetonitrile are added dropwise accompanied by ice-cooling to 92 g (0.5 mol) 2-acryloyloxyethyl methacrylate in 85 ml acetonitrile. After 48 h stirring at room temperature, the aminosilane has completely reacted. The solvent is evaporated off accompanied by the introduction of air at reduced pressure at the rotary evaporator at maximally 46° C. 132.2 g (98% yield) of a lightly-coloured clear oily liquid are obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][N:14]([CH3:25])[C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[CH3:13][N:14]([CH3:25])[C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][N:22]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:20])=[CH:23][CH:24]=1
Reactant: CN(C)c1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: CN(C)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(dimethylamino)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([OH:15])[CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.O1CCC[CH2:17]1.CC(C)([O-])C.[K+].CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([O:15][CH3:17])[CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccn(O)c1-c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COn1ccc(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of 2-(p-chlorophenyl)-1-hydroxypyrrole-3-carbonitrile (2.88 g, 0.0132 mol) and anhydrous tetrahydrofuran is added potassium tert-butoxide (1.55 g, 0.0138 mol). After 30 minutes, methyl iodide (2.06 g, 0.9 mL, 0.0145 mol) is added and the resulting slurry is stirred at room temperature for hours, diluted with water and extracted with ether. The combined ether extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid. Crystallization of the solid from ether/hexanes gives the title compound as a brown solid (2.35 g, 77%), mp 105°-106° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:31])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:32].CCN(C(C)C)C(C)C.C(Cl)Cl.[CH3:45][C@H:46]1[CH2:48][O:47]1>CO>[Cl:31][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:45][C@@H:46]([OH:47])[CH3:48])[C@H:3]([OH:32])[CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]2=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]2[N:18]=1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: C[C@H]1CO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC[C@H](C)O)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a solution of 2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 375B) (50 mg, 0.110 mmol) and DIPEA (0.031 mL, 0.221 mmol) in MeOH (0.5 mL)/DCM (0.5 ml) was added (S)-2-methyloxirane (64.1 mg, 1.104 mmol). The reaction was stirred for 16 hours. The solvents were removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 10-55% B over 25 minutes, then a 8-minute hold at 100% B; Flow: 20 mL/min Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(((S)-2-hydroxypropyl)amino)piperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (14.5 mg,).