Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:1][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[CH2:14][CH2:13]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A mixture of 3-formyl-benzonitrile (1.5 g, 11.45 mmol), N-methyl piperazine (1.49 g, 14.9 mmol) and NaBH(OAc)3 (3.63 g, 17.18 mmol) in DCM (75 ml) and CH3COOH (0.851 ml, 14.9 mmol) was stirred overnight at room temperature, then diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.5) to give 1.7 g of 3-(4-methyl-piperazin-1-ylmethyl)-benzonitrile.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][C:8]1[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=1[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](ON1C(=O)CCC1=O)=[O:17])=[O:11]>>[CH3:2][N:1]([C:16]([O:15][CH2:14][CH2:13][O:12][C:10]([C:9]1[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=1[CH3:7])=[O:11])=[O:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: Cc1ccccc1C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: CNCC(=O)O
Product: Cc1ccccc1C(=O)OCCOC(=O)N(C)CC(=O)O
Yield: 53.3 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.2 g, 2.24 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylbenzoate (0.6 g, 1.86 mmol) were reacted to provide 0.293 g (53.1% yield) of the title compound (39) as a white wax after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=7.81 (d, 1H), 7.40 (t, 1H), 7.22 (d, 2H), 7.01 (q, 1H), 4.1 (m, 2H), 3.0 (2s, 3H), 2.58 (s, 3H), 1.61-1.59 (2d, 3H). MS (ESI) m/z 318.07 (M+Na)+, 294.10 (M−H)−.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3]1.B.[O:22]1CCCC1.[OH-].[Na+].OO>O1CCCC1.O>[OH:22][CH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3]1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)C(c2ccccc2)C1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To solution of tert-butyl 4-methylene-2-phenylpiperidine-1-carboxylate (2.20 g, 8.04 mmol) in tetrahydrofuran (50 mL) at 0° C. was added borane-tetrahydrofuran complex (1M solution in tetrahydrofuran) (12.1 mL, 12.1 mmol) and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was allowed to warm to room temperature then stirred for an additional 2 hours. It was cooled to 0° C. and 2M aqueous sodium hydroxide (8.0 mL, 16.0 mmol) was added slowly followed by the slow addition of 30% aqueous hydrogen peroxide (5.5 mL, 48.4 mmol). The mixture was stirred for another hour then diluted with water (100 mL) and partitioned with ethyl acetate (250 mL). The organic layer was separated and washed with 2M aqueous sodium thiosulfate (100 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography in silica gel (chloroform:methanol 9:1 to 4:1) provided tert-butyl 4-(hydroxymethyl)-2-phenylpiperidine-1-carboxylate (1.86 g, 79%). 1H NMR (400 MHz, CDCl3): 7.30 (m, 2H), 7.20 (m, 3H), 4.86 (dd, 1H), 4.04 (m, 1H), 3.62 (m, 0.5H), 3.44 (m, 3H), 3.24 (m, 1H), 2.12 (m, 0.5H), 1.93 (m, 1H), 1.64 (m, 2H), 1.42 (m, 1H), 1.26 (s, 9H). GC/MS (EI) for C17H25NO3: 235 (M-tBu+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:14]=[CH2:13])=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: C=Cc1ccc([N+](=O)[O-])cc1
Product: O=CCc1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitrophenylacetaldehyde was prepared by the method described in Lethbridge et al., J. Chem. Soc. Perkin I, 35 1973) from p-nitrophenylethylene. The p-nitrophenylethylene was prepared by the method described in Strassburg et al., J. Am. Chem. Soc. 69:2142 (1947) from 1-bromo-2-(p-nitrophenyl)ethane commercially obtainable from Aldrich Chemical Co., Milwaukee, Wis.).
Reaction SMILES: [N:1]1([C:5]2[C:10]([F:11])=[C:9]([NH:12][NH2:13])[N:8]=[C:7]([CH2:14][CH3:15])[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH:16]1([CH2:21][C@H:22]([CH2:26][N:27]([CH:36]=[O:37])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23](O)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[N:1]1([C:5]2[N:6]=[C:7]([CH2:14][CH3:15])[N:8]=[C:9]([NH:12][NH:13][C:23](=[O:24])[C@H:22]([CH2:21][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:26][N:27]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:36]=[O:37])[C:10]=2[F:11])[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1nc(NN)c(F)c(N2CCC2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
4-(1-Azetidinyl)-2-ethyl-5-fluoro-6-hydrazinopyrimidine (88 mg, 0.42 mmol), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (140 mg, 0.46 mmol), and HOAt (56 mg, 0.42 mmol) were dissolved in 3 mL of DMF. Then, NMM (71 μL, 0.65 mmol) was added, followed by EDC (75 mg, 0.40 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-{2-[6-(1-azetidinyl)-2-ethyl-5-fluoro-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (160 mg, 76%). LCMS: (M+H)+: 499.4.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=2.[NH3:17].Cl>C1COCC1>[OH:3][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=2)[CH:11]=[C:2]([CH3:1])[N:17]=1
Reactant: COC(=O)c1ccc2cc(C)oc(=O)c2c1
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(C)nc(O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-methyl-1-oxo-1H-isochromene-7-carboxylate (1.0 g), 29% aqueous ammonia solution (30 mL) and THF (30 mL) was stirred at room temperature for 8 hours. The reaction mixture was neutralized with hydrochloric acid, and the precipitate was collected by filtration to obtain methyl 1-hydroxy-3-methylisoquinoline-7-carboxylate (390 mg).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:27])[C@@H:11]([NH:16]C(OCC1C=CC=CC=1)=O)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>CO.[Pd]>[ClH:28].[ClH:28].[CH2:1]([NH:8][CH2:9][CH:10]([OH:27])[C@@H:11]([NH2:16])[CH2:12][CH:13]([CH3:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(O)CNCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](N)C(O)CNCc1ccccc1

Procedure:
To a solution of 100 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane in 10 ml of diethyl ether were added 2 g of dry silica gel and 0.1 ml of benzylamine, and the mixture was stirred for 16 hours at room temperature, then heated under reflux for 2 hours. After filtration of the silica gel, the filtrate was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 56 mg of (3S)-N-benzyl-3-carbobenzoxyamino-2-hydroxy-5-methylhexylamine as a colorless viscous oil. To a solution of 54 mg of the amine compound obtained in 10 ml methanol was added 0.2 ml of a 2N-hydrochloric acid. The mixture was hydrogenated over 10 mg of palladium charcoal under hydrogen atmosphere. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 43 mg of (3S) -N-benzyl-3-amino-2-hydroxy-5-methylhexylamine dihydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:48]=[CH:47][C:36]([CH:37]([NH2:46])[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1>>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([NH:46][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:36]2[CH:47]=[CH:48][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccc(OC)cc2)cc1
Yield: 79 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4,4'-dimethoxybenzhydrylamine (prepared as described in Preparation 14) as starling materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 79%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([CH3:14])[CH2:10][C:11]2=[O:13])=[CH:6][CH:7]=1
Reactant: CC(CC(=O)O)Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: CC1CC(=O)c2cc(Br)ccc2C1
Temperature: 75 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 4-(4-bromophenyl)-3-methylbutanoic acid, prepared in a similar manner as described in Example 32 (6.43 g, 25.0 mmol), in H2SO4 (25 mL) was stirred at 75° C. for 3 h. The mixture was slowly poured onto ice. The resulting slurry was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 5.74 g (96%) of the title compound. 1H-NMR: 400 MHz, (CDCl3) δ: 8.10 (d, J=2 Hz, 1H), 7.54 (dd, J=8, 2 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 2.91 (d, J=16 Hz), 2.71 (d, J=13 Hz), 2.58 (m, 1H), 2.28 (m, 2H), 1.12 (d, J=6 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([F:26])[CH:18]=1>C(#N)C>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([F:26])[C:18]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Yield: 47.4 %

Procedure:
To a solution of 1.468 g of morpholine and 3.0 mL of diisopropylethylamine in 80 mL of acetonitrile was added a solution of 5.019 g of 2,6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate in 10 mL of acetonitrile. The mixture was heated to reflux for 5 hours, then cooled and concentrated in vacuo. The residue was purified on a silica gel column (3 cm tall, 10 cm diam), eluting with 25% ethyl acetate/hexanes (v/v) and then 2% acetic acid/25% ethyl acetate/hexanes to give 1.95 g of an orange oil. This was washed with 5% ethyl acetate/hexanes, and the bright yellow solids air dried, mp 91°-920° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:24][C@H:21]2[CH2:22][CH2:23][C@H:18]([O:17][CH3:16])[CH2:19][CH2:20]2)[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: CO[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Temperature: 150 °C

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (30.0 g, 88 mmol), trans-4-methoxycyclohexanamine (17.15 g, 133 mmol), N,N-diisopropylethylamine (30.8 mL, 177 mmol) and dimethylsulfoxide (70.8 mL) were combined in a reaction vial with a stirbar and heated in an oil bath at 150° C. for 16 h with stirring. The resulting mixture was diluted with ethyl acetate and the volatiles removed under reduced pressure. The residue was purified using silica gel chromatography on a Biotage SP1 (12% ethyl acetate in hexanes). Fractions containing the desired product were combined and organic volatiles removed under reduced pressure. The residue was triturated with 5% ethyl acetate in hexane. Solids were collected by vacuum filtration, washed with hexane and dried under vacuum to afford ethyl the title compound (15.37 g, 39.7 mmol, 44.8% yield) as an off-white solid. MS (ESI) m/z 387.0 [M]+, 389.0 [M+2]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[C:35]([CH3:48])=[C:36]([CH3:47])[C:37]4[O:41][C:40]([CH3:43])([CH3:42])[CH:39](O)[C:38]=4[C:45]=3[CH3:46])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCCCCC.C(OCC)(=O)C>CO>[C:2]1([NH:1][CH:39]2[C:38]3[C:45]([CH3:46])=[C:34]([N:31]4[CH2:30][CH2:29][N:28]([C:25]5[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=5)[CH2:33][CH2:32]4)[C:35]([CH3:48])=[C:36]([CH3:47])[C:37]=3[O:41][C:40]2([CH3:43])[CH3:42])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(Nc3ccccc3)C(C)(C)O4)CC2)cc1
Temperature: 60 °C
Reaction time: 120 h
Yield: 87.3 %

Procedure:
Aniline (120 mg, 1.29 mmol) and p-toluenesulfonic acid monohydrate (25.0 mg, 0.131 mmol) were added to a solution of 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol (260 mg, 0.656 mmol) obtained in Reference Example 18 in methanol (3 ml) and the mixture was stirred at 60° C. for 120 hours. The resulting mixture was concentrated under reduced pressure. The residue was made to basic with 1N aqueous potassium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with basic column chromatography (hexane then hexane/ethyl acetate=25/1) to obtain 270 mg (yield 87%) of the title compound via recrystallization (methanol). mp. 90–94° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([O:20]CC)=[O:19])[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1.[OH-].[Na+].S(=O)(=O)(O)O>C(O)C.ClCCl>[C:14]([O:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([Br:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:4]([C:18]([OH:20])=[O:19])=[C:5]2[CH2:10]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)c(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(Br)c(-c3cccc(F)c3)c(C(=O)O)c2C1
Temperature: 70 °C
Yield: 72.8 %

Procedure:
To a suspension of 2.41 g (5.16 mmol) of 2-tert-butyl 8-ethyl 6-bromo-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in 18 ml of ethanol are added 10.3 ml (10.3 mmol) of 1N sodium hydroxide solution and the mixture is heated at 70° C. for 2 days. The mixture is then taken up in dichloromethane and acidified by addition of 25 ml of aqueous 1N sulfuric acid. The organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure, to give a yellow solid, which is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 4% methanol in dichloromethane, to give 1.65 g of 2-(tert-butyloxycarbonyl)-6-bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid in the form of a pale yellow powder.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([CH3:34])[CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:20][CH:19]=1.BrB(Br)Br>>[NH2:26][CH2:25][C@@H:24]([C:21]1[CH:20]=[CH:19][C:18]([C:4]2[C:5]3[C:6]4[CH:17]=[CH:16][S:15][C:7]=4[C:8](=[O:14])[NH:9][C:10]=3[C:11]([CH3:13])=[CH:12][C:3]=2[OH:2])=[CH:23][CH:22]=1)[CH3:34]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: Cc1cc(O)c(-c2ccc([C@@H](C)CN)cc2)c2c1[nH]c(=O)c1sccc12
Yield: 52 %

Procedure:
Following General Procedure F, (R)-tert-butyl 2-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (43 mg, 0.095 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1.0 mL, 1.0 mmol) to afford the desired product (18 mg, 51%) as a grey solid: 1H NMR (300 MHz, DMSO-d6) δ 10.75-10.65 (m, 1H), 9.14 (s, 1H), 8.09 (s, 3H), 7.68 (d, J=5.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.05 (s, 1H), 5.86 (d, J=5.4 Hz, 1H), 3.27-2.95 (m, 3H), 1.38 (d, J=6.6 Hz, 3H); ESI MS m/z 365 [C21H20N2O2S+H]+; HPLC 98.6%, tR=8.42 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]2[N:33]([CH3:34])[CH2:32][CH2:31][N:30]([CH3:35])[C:29]2=[O:36])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]5[N:33]([CH3:34])[CH2:32][CH2:31][N:30]([CH3:35])[C:29]5=[O:36])[CH:25]=[CH:26][CH:27]=4)=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cnc(O)nn23)cc1
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)C1=O

Procedure:
3-{3-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a yellow foam (75 mg, 50%). LCMS (m/e) 491 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 8.38 (d, 2H, J=8.4 Hz), 8.05 (d, 2H, J=8.4 Hz), 7.68 (s, 1H), 7.51 (d, 1H, J=8.2 Hz) 7.37-7.29 (m, 1H), 7.11 (d, 1H, J=7.6 Hz), 7.08 (d, 1H, J=4.8 Hz), 6.91 (s, 1H), 6.86 (d, 1H, J=4.8 Hz), 3.75-3.65 (m, 1H), 3.66 (s, 1H), 3.25-3.18 (m, 1H), 3.10 (s, 3H), 3.08-3.00 (m, 1H), 2.99 (s, 3H), 2.77-2.67 (m, 1H), 2.18 (s, 3H).
Reaction SMILES: [I-].[NH2:2][C:3]1[S:4][C:5]2[CH:12]=[C:11]([C:13]3[S:14][C:15]4[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:9][C:6]=2[N+:7]=1[CH3:8].O.[OH-].[Na+]>CS(C)=O>[NH:2]=[C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][C:11]([C:13]3[S:14][C:15]4[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:12][C:5]=2[S:4]1
Reactant: Cc1ccc2nc(-c3ccc4c(c3)sc(N)[n+]4C)sc2c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2nc(-c3ccc4c(c3)sc(=N)n4C)sc2c1
Yield: 89.7 %

Procedure:
2-amino-3-methyl-6-(6-methyl-benzothiazol-2-yl)-benzothiazolium iodide (0.3 g, 0.68 mmol) was taken up in DMSO (10 ml). Water was added (20 ml) and the mixture was basified to pH 10 with aqueous NaOH (20%). The precipitate was collected by filtration and washed with water to produce 3 as a light yellow solid (0.19 g, 89%). Mp 146-148° C.; 1H NMR (DMSO): 2.45 (3H, s, Ar—CH3), 3.38 (3H, s, N—CH3), 7.16 (1H, d, J=8.4, ArH), 7.33 (1H, d, J=8.4, ArH), 7.87 (1H, s, ArH), 7.90 (1H, s; ArH), 7.93 (1H, d, J=8.4, ArH), 8.16 (1H, s, ArH), 8.55 (1H, s, NH); 13C NMR analysis was not possible due to poor solubility of 4 in available deuterated solvents; HR-FAB-MS m/z Found: 312.0619 C16H14N3S2 (M+H+): requires M, 312.0629.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.[CH:19](OC)=[O:20]>>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[CH:19]=[O:20]
Reactant: COC=O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C=O
Yield: 77.4 %

Procedure:
To a suspension of (2S,4R)-4-hydroxyproline methyl ester hydrochloride (9.08 g, 50.0 mmol) in methyl formate (90.0 ml) was added triethylamine (11.85 ml, 85.0 mmol). The mixture was refluxed for 5 h. The precipitate was filtered off, and the filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=4:1→3:2) to give (2S,4R)-N-formyl-4-hydroxyproline methyl ester (6.70 g, yield: 77.4%).
Reaction SMILES: Cl.C(OC(=O)[N:8]([C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[CH:22][C:23]([N:25]([CH3:43])[C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([S:39](=[O:42])(=[O:41])[NH2:40])[CH:34]=4)[N:27]=3)=[CH:24][C:17]=2[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH3:43][N:25]([C:23]1[CH:22]=[CH:21][C:18]2[N:19]([CH3:20])[C:15]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:16][C:17]=2[CH:24]=1)[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]2[CH:34]=[C:35]([S:39]([NH2:40])(=[O:42])=[O:41])[CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ccc2c(c1)nc(Nc1ccccc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1

Procedure:
(1-Methyl-5-{methyl-[2-(3-sulfamoyl-phenylamino)-pyrimidin-4-yl]-amino}-1H-benzoimidazol-2-yl)-phenyl-carbamic acid tert-butyl ester hydrochloride was stirred in solution of 50% trifluoroacetic acid and methylene chloride and concentrated to give the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.32 (br s, 1H), 9.54 (br s, 1H), 8.49 (s, 1H), 7.86 (d, J=6.9 Hz, 1H), 7.73-7.78 (m, 3H), 7.47-7.54 (m, 3H), 7.34-7.41 (m, 4H), 7.06-7.14 (m, m 2H), 5.80 (d, J=6.6 Hz, 1H), 3.78 (s, 3H), 3.53 (s, 3H). MS (ESI) m/z=501 [M+H]+.