Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])(=[O:10])=[O:9])[CH2:5][C:4]2[CH:20]=[C:21]([C:23]([OH:25])=O)[S:22][C:3]1=2.CCN(C(C)C)C(C)C.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][C:2]1([CH3:26])[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])(=[O:9])=[O:10])[CH2:5][C:4]2[CH:20]=[C:21]([C:23]([NH:43][O:42][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)=[O:25])[S:22][C:3]1=2
Reactant: CC1(C)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cc(C(=O)O)sc21
Reactant: NOC1CCCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cc(C(=O)NOC3CCCCO3)sc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A solution of 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (20 g, 50 mmol) was cooled to 0° C. DIPEA (32.3 g, 250 mmol) was added and the solution was stirred at 0° C. for 30 minutes. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (5.8 g, 50 mmol) and HATU (22.8 g, 60 mmol) were then added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was washed with water, brine and dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (20-50% EtOAc/hexane) to afford product (23.5 g, 94%). LCMS (FA) ES+ 496; 1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.10 (dd, J=7.7, 1.5 Hz, 1H), 8.02 (dd, J=7.7, 1.5 Hz, 1H), 7.90 (dtd, J=17.6, 7.5, 1.4 Hz, 2H), 7.41 (s, 1H), 4.92 (s, 1H), 4.33 (s, 2H), 4.00 (s, 1H), 3.50 (d, J=11.1 Hz, 1H), 3.38 (s, 2H), 1.72 (d, J=22.2 Hz, 3H), 1.53 (s, 3H), 1.27 (s, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH2:9].C(N1CCCCC1)C.ClC1C([O:27][C:28](=O)[C@H:29]([CH2:41][CH2:42][C:43](=[O:45])[NH2:44])[NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=C(Cl)C(Cl)=C(Cl)C=1Cl>CN(C)C=O.ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH:9][C:28](=[O:27])[C@H:29]([CH2:41][CH2:42][C:43](=[O:45])[NH2:44])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: COC(=O)CNC(=O)CN
Agent: CCN1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of glycyl-glycine methyl ester hydrochloride (1.9 g; 10 mmoles) in a dimethylformamide-dichloromethane (1:2) mixture (30 ml) is admixed with N-ethylpiperidine (1.4 ml) and stirred for 2 hours at room temperature. After that benzyloxycarbonylglutamine pentachlorphenyl ester (5.3 g; 10 mmoles) is added and the reaction mixture is stirred at room temperature a further 4 hours. After 8 hours of standing, the precipitated crystalline product is separated and crystallized from methanol - dichloromethane. Yield 2.5 g (61%), m.p. 129°-134° C., after additional crystallization from methanol 132°-134° C. Rf 0.57/S1, 0.78/S2⟦alpha⟧sub.D20 -8.5° (c 0.2; 50% acetic acid). Composition: C18H24N4O7.1/2H2O.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH3:12])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:7]([O:6][C:4](=[O:5])[CH2:3][CH:2]([O:1][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])[CH2:11][CH3:12])([CH3:8])([CH3:10])[CH3:9]
Reactant: CCC(O)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCC(CC(=O)OC(C)(C)C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.9 %

Procedure:
A solution of t-butyl 3-hydroxypentanoate (5.22 g, 0.3 mol) in dry pyridine (10 ml) was treated with p-toluenesulfonyl chloride (6.3 g, 0.33 mol) dissolved in dry pyridine (15 ml). The resulting solution was stirred at room temperature for 24 h and poured into ice-water (300 ml). The oily layer was separated and dissolved in ether (140 ml). This solution was washed with water (3×150 ml) and dried over anhydrous MgSO4. Evaporation of the ether under reduced pressure gave an oil (7.75 g, 78.7%). ir (neat) νmax : 1725 (C=O of ester) and 1178 cm-1 (sulfonate); 1Hmr (CDCl3) δ: 0.80 (3H, t), 1.38-1.78 (2H, m), 1.42 (9H, s), 2.32-2.62 (2H, m), 2.38 (3H, s), 4.82 (H, m), 7.25 (2H, d) and 7.70 ppm (2H, d). Anal. calcd for C15H24O5S: C 56.94, H 7.65; found: C 58.39, H 7.54.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>>[CH3:3][CH:2]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: Oc1ccccc1Br
Product: CC(C)CCCC(C)Oc1ccccc1Br

Procedure:
In the same manner as Example 1: 2-bromo- 6-methyl-heptane was reacted with o-bromo-phenol to obtain o-bromo-phenyl 1,5-dimethyl-hexyl ether (boiling point = 190°-193°C/17 mmHg);
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[F:7][C:8]([F:29])([F:28])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([CH2:3][C:4]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:18]2[N:19]=[CH:20][N:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][C:8]([F:7])([F:29])[F:28])=[CH:11][CH:12]=3)[N:17]=2)=[CH:22][CH:23]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Cyanoacetic acid (0.30 g, 3.53 mmol) and 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (1.00 g, 3.12 mmol) were dissolved in 30 mL of dichloromethane, and then dicyclohexylcarbodiimide (0.695 g, 3.37 mmol) was added in one portion as a solid. The solution was allowed to stir for 2 h, then the solvent was removed and the residue was heated in 75 mL of EtOAc, cooled and filtered to remove dicyclohexyl urea. The filtrate was concentrated and the solid was recrystallized from EtOH to give 0.82 g (66%) of 2-cyano-N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetamide (B11) as a white solid, mp 250-252° C. 1H NMR (DMSO-d6) δ 10.51 (s, 1H), 9.39 (s, 1H), 8.13-8.00 (m, 4H), 7.75-7.66 (m, 2H), 7.62 (d, J=8.3 Hz, 2H), 3.95 (s, 2H). ESIMS m/z 388 (M+H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:34]=[N:35][N:36]([CH:38]5[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]5)[CH:37]=4)=[CH:29][N:28]=3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:17]1.CCN(C(C)C)C(C)C.[O:53]1[CH2:56][C:55](=O)[CH2:54]1>ClCCCl>[CH3:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3[N:28]=[CH:29][C:30]([C:33]4[CH:34]=[N:35][N:36]([CH:38]5[CH2:43][CH2:42][N:41]([CH:55]6[CH2:56][O:53][CH2:54]6)[CH2:40][CH2:39]5)[CH:37]=4)=[CH:31][N:32]=3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:17]1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)cn1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C6COC6)CC5)c4)cn3)c2)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Sodium triacetoxyborohydride (0.13 g; 0.62 mmol; 2.0 eq.) was slowly added to a solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidine (example 1,200 mg; 0.31 mmol; 1.0 eq.), DIEA (53 μl; 0.31 mmol; 1.0 eq.) and 3-oxetanone (39 μl; 0.62 mmol; 2.0 eq.) in DCE (4 mL). The reaction mixture was then stirred at 50° C. for 3 h. It was then quenched by addition of water. Aqueous phase was basified to pH 12 and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige powder (100 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.59-8.50 (m, 2H), 8.27 (s, 1H), 8.25-8.18 (m, 1H), 8.18-8.11 (m, 1H), 7.96-7.89 (m, 1H), 7.77-7.66 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 4.23 (s, 1H), 3.90 (s, 3H), 3.51-3.40 (m, 1H), 2.87-2.73 (m, 2H), 2.17-1.90 (m, 6H). HPLC (Condition A): Rt 2.49 min (purity 97.2%). MS (ESI+): 442.5.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])([C:6]2[N:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)O)[CH2:3][CH2:2]1.[Br:19][Si](C)(C)C.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:19][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccccc1C(O)(c1cccn1C)C1CC1
Reactant: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=CCCBr)c1cccn1C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
Cyclopropyl-(2-methylphenyl)-(N-methylpyrrol-2-yl)methanol (9.9 g, 0.041 mole) was dissolved in dichloromethane (250 ml) and cooled to -70° C. under nitrogen. Bromotrimethylsilane (6.4 g, 0.042 mole) in dichloromethane (250 ml) was added within 30 min. The reaction mixture was stirred at -70° C. for another 90 min. Pyridine (3.5 ml) was added and when the mixture had reached room temperature, saturated sodium bicarbonate solution (100 ml) was added. The phases were separated and the organic phase was dried (MgSO4) and evaporated leaving the title compound as an oil (10.9 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24](CC(=O)C)[CH:23]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH:35][CH2:36][CH2:37][CH2:38][C:39]#[C:40]C1C=CC(C(O)=O)=CC=1>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:23]=[CH:24][C:25]([C:40]#[C:39][CH2:38][CH2:37][CH2:36][OH:35])=[CH:26][CH:27]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: O=C(O)c1ccc(C#CCCCO)cc1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C#CCCCO)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using Intermediate 21 in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C28H36N5O3+ 490.3. found m/z=490.4 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[Cl:14][C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>[OH-].[Na+].C1COCC1>[Cl:14][C:15]1[S:19][C:18]([S:20]([NH:1][CH:2]([CH:6]2[CH2:11][CH2:10][C:9]([F:12])([F:13])[CH2:8][CH2:7]2)[C:3]([OH:5])=[O:4])(=[O:22])=[O:21])=[CH:17][CH:16]=1
Reactant: NC(C(=O)O)C1CCC(F)(F)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(NS(=O)(=O)c1ccc(Cl)s1)C1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
The amino(4,4-difluorocyclohexyl)acetic acid (2.68 g, 10.973 mmol) was dissolved in 2N NaOH (20 mL). The solution was cooled to 0° C., 5-chlorothiophene-2-sulfonyl chloride (3.25 g, 12.42 mmol) was added (5 min) dropwise as a solution in THF (10 mL). The solution was allowed to warm up to 25° C. overnight. After 19 h, THF was removed in vacuo and the mixture was acidified to a pH of about 1 to about 2 with 2N HCl (20 mL). The aqueous layer washed with EtOAc (4×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to produce {[(5-chlorothien-2-yl)sulfonyl]amino}(4,4-difluorocyclohexyl)acetic acid as a crude oil (3.8 g, 98.2%). Mass Spectrum (−ESI): 372 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:26][CH3:27])[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:5]2[CH:6]=[C:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[Cl:28])[C:2]([Cl:1])=[CH:3][C:4]=2[O:26][CH3:27])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of tert-butyl 4-(2-(4-chloro-5-iodo-2-methoxyphenylamino)acetyl)piperazine-1-carboxylate (200 mg, 0.4 mmol) and 2-chlorophenylboronic acid (69 mg, 0.44 mmol) in 1,4-dioxane (10 mL) and water (2 mL), Pd(PPh3)4 (40 mg, 0.035 mmol) and Na2CO3 (212 mg, 2 mmol) were added. The mixture was stirred at 80° C. for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford the desire product (150 mg, 76% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: COc1cccc(C(=O)CBr)c1
Product: COc1cccc(C(=O)COC(=O)CC2CCCCN2C(=O)OC(C)(C)C)c1
Yield: 95.2 %

Procedure:
The title compound (3.06 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-bromo-3′-methoxyacetophenone (1.88 g) according to the method of description 36.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (521 mg, 2.8 mmol) in DCM (6 ml) was added NEt3 (547 μl, 3.92 mmol, 1.4 eq.) and 4-trifluoromethoxy-benzenesulfonyl chloride (880 mg, 3.36 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 12 hrs. The excess of sulfonyl chloride was quenched by addition of trisamine resin (150 mg), and subsequent stirring for 2 hrs. The resin was then filtered off, and NaHCO3 sat (5 ml) was added. Filtration of the resulting mixture through hydrophobic catridge and subsequent removal of the solvent under reduced pressure afforded the desired 4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester in quantitative yield.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.CS(O)(=O)=O.[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][N:37]([CH3:41])[CH2:38]2)=[CH:34][C:33]=1[NH2:42]>COCC(O)C>[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][N:37]([CH3:41])[CH2:38]2)=[CH:34][C:33]=1[NH:42][C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: COc1cc2c(cc1N)CN(C)C2
Agent: CS(=O)(=O)O
Solvent: COCC(C)O
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n1)CN(C)C2
Temperature: 135 °C
Reaction time: 24 h

Procedure:
N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (90.00 mg, 0.247), methanesulfonic acid (0.048 mL, 0.74 mmol) and 6-methoxy-2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (88.03 mg, 0.494 mmol) were combined in 1-methoxy-2-propanol (1.45 mL) in a capped tube and the reaction was stirred at 135° C. for 24 h. The product was isolated by reverse phase hplc and neutralization to the free amine to afford N-{2-[2-(6-methoxy-2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a brown amorphous solid (5 mg, 4%). 1H-NMR (CDCl3) δ 8.72 (s, 1H), 8.02 (s, 1H), 7.90 (m, 1H), 7.52 (m, 4H), 7.03 (d, J=4.5 Hz, 1H), 6.86 (d, J=4.5 Hz, 1H), 6.72 (s, 1H), 3.89 (m, 2H), 3.88 (s, 3H), 3.74 (m, 2H), 3.11 (s, 3H), 2.67 (s, 3H), 2.60 (s, 3H); LC/MS (ESI+): 479.1 (M+H).
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][C:19]([NH:21][C:22]1[C:39]([OH:40])=[C:38]2[C:25]([CH2:26][CH:27]3[C:36]([C:37]2=[O:41])=[C:35]([OH:42])[C:34]2([OH:43])[CH:29]([CH:30]([N:49]([CH3:51])[CH3:50])[C:31]([OH:48])=[C:32]([C:45]([NH2:47])=[O:46])[C:33]2=[O:44])[CH2:28]3)=[C:24]([N:52]([CH3:54])[CH3:53])[CH:23]=1)=[O:20]>CN1C(=O)N(C)CCC1.C(#N)C>[CH2:2]([N:9]([OH:10])[CH2:18][C:19]([NH:21][C:22]1[C:39]([OH:40])=[C:38]2[C:25]([CH2:26][C@@H:27]3[C:36]([C:37]2=[O:41])=[C:35]([OH:42])[C@@:34]2([OH:43])[C@H:29]([C@H:30]([N:49]([CH3:51])[CH3:50])[C:31]([OH:48])=[C:32]([C:45]([NH2:47])=[O:46])[C:33]2=[O:44])[CH2:28]3)=[C:24]([N:52]([CH3:53])[CH3:54])[CH:23]=1)=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Reactant: ONCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: CN(C)c1cc(NC(=O)CN(O)Cc2ccccc2)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Yield: 36.8 %

Procedure:
The compound of the example is prepared by the procedure of Example 1 using 3 g of N-benzylhydroxylamine hydrochloride, 2 g of sodium carbonate, and 0.8 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 10 ml DMPU and 3 ml acetonitrile to give 0.315 g of the product.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C@H:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6][C:7]([O:9][CH3:10])=[O:8].C=O.[C:21](O)(=O)C.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:3]=1[CH2:4][C@H:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:21]2
Reactant: CC(=O)O
Reactant: COC(=O)N[C@H](Cc1ccccc1Br)C(=O)OC
Agent: C=O
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1Cc2c(Br)cccc2CN1C(=O)OC
Yield: 91.2 %

Procedure:
Stir a mixture of methyl 2-bromo-N-(methoxycarbonyl)-D-phenylalaninate (29.1 g, 92.10 mmol) and paraformaldehyde (9.13 g, 101.3 mmol) in glacial acetic acid (115 mL, 2.01 mol) and concentrated sulfuric acid (38.4 mL, 719.9 mmol) at room temperature for 7 hours. Partition between water and ethyl acetate. Separate the layers and extract the aqueous layer with ethyl acetate. Combine the ethyl acetate extracts and dry over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (27.6 g, 84.0 mmol). MS (m/z): 328 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][C:20]([N:29]([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)(=[O:3])[CH3:2].[Si]([Cl:36])(C)(C)C>C(OCC)(=O)C>[ClH:36].[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][C:20]([N:29]([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)OCCCc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
3-(2-(4-(Dimethylamino)-4-phenylcyclohexyl)-1H-indol-3-yl)propyl acetate (more polar diastereomer) (60 mg, 0.16 mmol) was dissolved in ethyl acetate (20 ml). Me3SiCl (40 μl, 0.32 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (1×5 ml) and then dried. Example 185 (55 mg, m.p. 229-232° C., 84%) was a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[NH:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:15]([C:24](O)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C@@H:15]([NH:14][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:24](=[O:25])[N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: c1ccc(CN2CCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccn2)CC1

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-oxo-2-[4-(2-pyridylmethyl)piperazinyl]ethyl}(tert-butoxy) carboxamide was prepared according to the procedure for Preparation XIX using (2-pyridylmethyl)piperazine (650 mg. 3.7 mmol) (Array), Boc-p-Cl-D-Phe-OH (1.1 g, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (2.2 g, 7.2 mmol), HOAT (560 mg, 4.10 mmol) and DMF (15 mL) (730 mg). MS (ESI, pos. ion) m/z: 459 (M+H), (ESI, neg. ion) m/z: 457 (M−H). Calc'd for C24H31ClN4O3: 458.98.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:35]([O:37]C)C=CC=1B(O)O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:37][CH3:35])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 2-chloro-4-methoxyphenylboronic acid and making non-critical variations provided the title compound as an off-white amorphous solid. IR (diffuse reflectance) 2969, 2934, 1604, 1568, 1550, 1482, 1448, 1439, 1392, 1287, 1228, 1203, 1180, 1045, 740 cm−1; OAMS supporting ions at: ESI+ 423.9; MS (CI) m/z 424 (MH+); HRMS (FAB) calcd for C24H26CLN3O2+H1 424.1792, found 424.1789. Anal. Calcd for C24H26ClN3O2: C, 68.00; H, 6.18; N, 9.91. Found: C, 67.86; H, 6.29; N, 9.79.