Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][NH:6][CH2:5]2.CC1C=CC(S(O)(=O)=O)=CC=1.Cl.[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44](O)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44]([N:6]1[CH2:7][CH2:8][C:9]2=[N:1][N:2]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]2[CH2:5]1)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)Cn1cc2c(n1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: CCOC(=O)Cn1cc2c(n1)CCN(C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C2

Procedure:
In the same manner as in Example I-(1-A) except for using 0.30 g (0.79 mmol) of ethyl 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate.TsOH in place of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-acetate.HCl, 0.20 g (0.79 mmol) of N-t-butoxycarbonyl-L-phenylalanine in place of N-t-butoxycarbonyl-L-4-nirophenylalanine and 0.33 g (0.87 mmol) of HBTU in place of BOP, the reaction was carried out to obtain ethyl 5-(N-t-butoxycarbonyl-L-phenylalanyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate as pale brownish solid without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)(=O)=O)=[N:19][CH:20]=2)[N:15]([CH3:27])[C:14]1=[O:28].[CH3:29][C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[C:31]=1[NH2:32].C([O-])(C)(C)C.[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:32][C:31]3[C:33]([N+:37]([O-:39])=[O:38])=[CH:34][CH:35]=[CH:36][C:30]=3[CH3:29])=[N:19][CH:20]=2)[N:15]([CH3:27])[C:14]1=[O:28]
Reactant: COc1cc(OC)c(Cl)c(N2Cc3cnc(S(C)(=O)=O)nc3N(C)C2=O)c1Cl
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(N2Cc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3N(C)C2=O)c1Cl
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a mixture of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (450 mg, 1.01 mmol) and 2-methyl-6-nitroaniline (230 mg, 1.51 mmol) in 5 mL of N,N-dimethylformamide was added potassium tert-butanolate (339 mg, 3.02 mmol) at RT and stirred for 0.5 h. LCMS showed the reaction was completed. The mixture was quenched by 80 mL of water, and the precipitate was collected via the filtration and dried to give the title compound (290 mg, 56%) as a yellow solid, which was directly used in the next step without further purification. MS (ES+) C22H20Cl2N6O5 requires: 518, 520. found: 519, 521 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16](F)[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[C:6]=1[F:24])[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:13]=2[CH3:23])[C:6]=1[F:24])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.Cl>CN(C=O)C>[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[C:5]([OH:4])=[O:30])[CH2:16][CH2:17]3)=[CH:22]2)=[CH:34][CH:33]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3ccc(F)cc3)c3ccccc23)CC1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
0.02 g (0.42 mmol) of a dispersion of 60% NaH in mineral oil were added to a solution of 0.06 g (0.15 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester prepared in step D in 1 mL of anhydrous DMF under nitrogen atmosphere. After stirring 30 minutes at room temperature 0.026 mL (0.21 mmol) of 4-fluoro-benzyl bromide were added and the mixture was stirred for 18 hours. After addition of 0.09 g (0.12 mmol) of 3-(3-mercapto-phenyl)-propanamido-methyl-polystyrene in 1 mL of DMF the mixture was stirred overnight at room temperature. 0.1 mL of 2N HCl were added to the reaction mixture and the crude-was filtered. The solvent was removed under reduced pressure and the crude mixture was purified using a 500 mg Varian C18 chromatography column affording 0.059 g (84% yield) of 2-(2-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[CH2:1]([C:4]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH3:3]
Reactant: CCCc1c(C(=O)OCC)nc2ccccc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(C(=O)OCC)nc2ccccc2c1OCc1ccccc1

Procedure:
A well-stirred mixture of 5 parts of ethyl 3-n-propyl-4-hydroxyquinoline-2-carboxylate, 3 parts of anhydrous potassium carbonate and 3.3 parts of benzyl bromide in anhydrous acetone was boiled under reflux for 16 hours, filtered to remove inorganic salts, and evaporated to remove solvent. A solution of the residual oil in 75 parts of ether, after being washed with N.sodium hydroxide (2 portions each comprising 25 parts) and then water (4 portions each of 40 parts) was dried over magnesium sulphate and evaporated to yield 6.4 parts of crude ethyl 3-n-propyl-4-benzyloxyquinoline-2-carboxylate as a very pale yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl>CN1CCCC1=O.C(O)C.[Ni](Cl)Cl.[Zn]>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[S:30]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: C1COCCN1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [I-]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: O=S(=O)(c1cc(Cl)ccc1Cl)N1CCOCC1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Anhydrous nickel(II) chloride (60 mg, 0.46 mmole), triphenylphosphine (800 mg, 3.05 mmole), sodium iodide (180 mg, 1.2 mmole), and activated zinc powder (1.2 g, 18 mmole) are placed into a 25 ml flask under an inert atmosphere along with 7 ml of anhydrous N-methylpyrrolidinone (NMP). This mixture is stirred at 50° C. for about 10 minutes, leading to a deep-red coloration. A solution of 3.4 g (11.5 mmole) of 2,5-dichlorobenzenesulfonylmorpholine, which is prepared by the reaction of 2,5-dichlorobenzenesulfonyl chloride with morpholine, in 8 ml of anhydrous NMP is then added by syringe. After stirring for 60 hours, the resulting highly viscous solution is poured into 100 ml of 1 molar hydrochloric acid in ethanol to dissolve the excess zinc metal and to precipitate the polymer. This suspension is filtered and triturated with acetone to afford, after isolation and drying, solid polyparabenzenesulfonylmorpholine.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)c1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and m-toluidine (25.8 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3-methylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (18.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.C(=O)([O-])O.[Na+]>[Br-].[K+].CO>[Br:16][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: Clc1ccn2ccnc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Product: Clc1ccn2c(Br)cnc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
7-Chloroimidazo[1,2-α]pyridine (3.0 g, 19.7 mmol) and sodium acetate (1.94 g, 23.6 mmol) were dissolved in a saturated solution of potassium bromide in methanol (25 ml) and cooled to 0° C. before adding bromine (3.3 g, 20.7 mmol) dropwise over 5 min. The mixture was allowed to stir for 15 min before pouring onto saturated sodium hydrogencarbonate solution (200 ml). The resulting solid was collected by filtration and dried under high vacuum to give 3-bromo-7-chloroimidazo[1,2-α]pyridine (3.64 g, 80%) as a white solid. 1H NMR (360 MHz, CDCl3) δH 6.92 (1H, dd, J 2 and 7), 7.61 (1H, s), 7.63 (1H, d, J 2), 8.05 (1H, d, J 7).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](=O)[CH2:32][CH2:33][CH3:34]>CO.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: CCCC=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (165 mg, 0.415 mmol) and butyraldehyde (50 mg, 0.69 mmol) in MeOH (4 mL) was heated at reflux for 30 minutes. The solution was allowed to cool to room temperature, 10% Pd/C (20 mg, 0.019 mmol) was added, and the mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 20 h. The mixture was filtered through Celite and the solvent from the filtrate was removed under reduced pressure. Purification of the crude material by column chromatography on silica gel (200:5:1 CH2Cl2/MeOH/NH4OH) afforded AMD9701 (16 mg, 8%) as a colourless foam. 1H NMR (CDCl3) δ 0.87 (m, 3H), 1.24-1.49 (m, 4H), 1.68 (m, 1H), 2.02 (m, 2H), 2.26 (m, 1H), 2.56 (m, 2H), 2.79 (m, 2H), 3.68 (s, 2H), 3.73 (s, 2H), 3.97 (d, 1H, J=17 Hz), 4.08 (m, 1H), 4.17 (d, 1H, J=17 Hz), 7.18 (m, 5H), 7.35 (m, 2H), 7.42 (m, 1H), 7.58 (m, 2H), 8.69 (d, 1H, J=3.9 Hz); 13C NMR (CDCl3) δ 14.39, 20.84, 21.79, 23.77, 29.63, 32.57, 48.88, 49.53, 54.11, 60.58, 111.30, 119.11, 121.68, 122.04, 122.60, 128.47, 128.99, 135.09, 137.55, 138.30, 139.82, 147.33, 156.73, 157.89. ES-MS m/z 454 (M+H). Anal. Calcd. for C29H35N5.1.3H2O: C, 73.02; H, 7.94; N, 14.68. Found: C, 73.06; H, 7.70; N, 14.32.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([SH:23])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(C(C)=O)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:23][C:19]2[N:18]=[C:17]([OH:16])[CH:22]=[CH:21][N:20]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: Oc1ccnc(S)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCc1c(CSc2nccc(O)n2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 23.7 %

Procedure:
To a mixture of 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride, 0.20 g of 4-hydroxy-2-mercaptopyrimidine, 0.20 g of anhydrous potassium carbonate and 4 ml of methyl ethyl ketone was added a catalytic amount of tetra-n-butylammonium bromide. The mixture was stirred at 60° C. for 1 day. A 1N aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was applied to silica gel column chromatography. Elution with a mixture of hexane-ethyl acetate (1:2) gave 0.10 g of 2-[(4-acetyl-3- hydroxy-2-propylbenzyl)thio]-4-hydroxypyrimidine.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[C:20]([N+:30]([O-:32])=[O:31])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:33].CCOCC>CC(O)=O>[BrH:33].[BrH:33].[CH3:29][CH:26]1[CH2:27][CH2:28][N:23]([C:21]2[C:20]([N+:30]([O-:32])=[O:31])=[CH:19][CH:18]=[C:17]([N:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)[N:22]=2)[CH2:24][CH2:25]1
Reactant: CC1CCN(c2nc(N3CCN(C(=O)OCc4ccccc4)CC3)ccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1CCN(c2nc(N3CCNCC3)ccc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A solution of 4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazine-1-carboxylic acid benzyl ester (as prepared in the previous step, 3.2 g, 7.3 mmol) in HOAc (50 mL) was treated with 30% HBr in HOAc (7.3 mL, 1 mL/mmol benzyl ester) and heated to 60° C. for 1 h. The reaction was cooled to room temperature and allowed to stir for 5 h, after which time Et2O was added to the reaction while stirring. The bright yellow precipitate was filtered and washed with Et2O to afford the title compound (2.6 g, 77%). 1H-NMR (CD3OD; 400 MHz): δ 8.44 (d, 1H, J=9.6 Hz), 6.95 (d, 1H, J=9.6 Hz), 4.13 (app t, 4H, J=5.2 Hz), 3.87-3.79 (m, 2H), 3.71-3.60 (m, 2H), 3.42 (app t, 4H, J=5.2 Hz), 2.09-2.00 (m, 2H), 1.99-1.88 (m, 1H), 1.69-1.55 (m, 2H), 1.09 (d, 3H, J=6.8 Hz). LC-MS (ESI, m/z): Calcd. for C15H23N5O2, 306.2 (M+H), found 306.1.
Reaction SMILES: C(=O)=O.C(#N)C.[C:7]([C:9]1[N:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)#[N:8].[Br:22]N1C(C)(C)C(=O)N(Br)C1=O>C(#N)C.CCOC(C)=O>[Br:22][C:12]1[CH:13]=[C:9]([C:7]#[N:8])[N:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH:11]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nn1cccc1C#N
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nn1cc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple and thermocontroller, and dry-ice acetonitrile cooling. 2-Cyano-pyrrol-1-yl-carbamic acid, tert-butyl ester (20 g, 96.5 mmol) was added and dissolved in 350 mL acetonitrile and cooled to below −30° C. 1,3-Dibromo-5,5-dimethylhydantoin (13.79 g, 48.26 mmol) was added as a solid, and the reaction was allowed to warm to rt over 2 h. Analysis by RP-HPLC at 2 h indicated that about 10% starting material remained. The reaction was cooled again to below −30° C. and treated with additional 1,3-dibromo-5,5-dimethylhydantoin (1.3 g, 4.8 mmol). The reaction was allowed to warm slowly to rt over 3 h. The reaction was diluted with 500 mL EtOAc and transferred to a separatory funnel. The organic layer was washed with 1N aq sodium carbonate, water and brine and then dried with sodium sulfate. Filtration of the organic layer through silica gel removed much of the colored impurities. Evaporation of the solvent under vacuum provided reddish oil, which provided orange-brown crystals of the desired product upon seeding (27.16 g, 98%). 1H-NMR (DMSO): δ 10.95 (bs, 1H), 7.61 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=2 Hz), 1.44 (s, 9H, J=4.4, 1.7 Hz). MS: LC/MS (+esi), m/z=[M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([C:14](=[O:30])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[C:16]=3[F:29])=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].O.[OH-].[Li+].Cl>O1CCCC1>[F:29][C:16]1[C:17]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:14]([C:13]1[C:7]2[C:8](=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:12]=1)=[O:30]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)OC)cc23)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)O)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-1552, 80.0 mg, 0.18 mmol) in tetrahydrofuran (10.0 mL) were added water (3.0 mL) and lithium hydroxide (82 mg, 3.4 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water, acidified with 1 N HCl to pH around 1, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and washed with ethyl acetate to give an off-white solid (P-1559, 60 mg, 77%) MS (ESI) [M+H+]+=424.2.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][NH:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])=[O:9]>C(O)(=O)C>[ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9]
Reactant: CC(C)(C)OC(=O)CNNC(=O)Cc1cccs1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CNNC(=O)Cc1cccs1

Procedure:
Gaseous HCl is passed into a stirred and cooled suspension of 3.2 g of the compound from Example 7 in 30 ml of glacial acetic acid until saturated. The mixture is then stirred for 1 h and the volatile fractions are removed in vacuo. The residue is recrystallized from ether.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[S:44][C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)=[CH:46][N:47]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[S:44][C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)=[CH:46][N:47]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COCc1ncc(Cn2ncc(N)n2)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COCc1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (30.0 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (4.8 mg, 0.04 mmol), HOBt (26 mg, 0.19 mmol), EDC (76 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.63 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 2-((2-(methoxymethyl)thiazol-5-yl)methyl)-2H-1,2,3-triazol-4-amine (36 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the reaction mixture was stirred overnight at rt. The solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a beige solid. TLC: rf (4:6 hept-EA)=0.30. LC-MS-conditions 07: tR=0.87 min, [M+H]+=397.39.
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5](=[O:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC>ClCCl.O.OC1C2N=NNC=2C=CC=1>[OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:10]2[CH:6]([CH2:7][N:8]([C:36](=[O:37])[CH2:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH3:27])[CH2:9]2)[C:5](=[O:11])[CH2:4][CH2:3]1
Reactant: COc1ccccc1C1(O)CCC(=O)C2CNCC21
Reactant: COc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
To a solution of 2.8 g of (3aRS,7RS,7aSR)-7-hydroxy-7-(2-methoxyphenyl)-4-perhydroisoindolone and 1.3 cm3 of triethylamine in 60 cm3 of anhydrous dichloromethane are added 1.55 g of (2-methoxyphenyl)acetic acid, 0.03 g of hydroxybenzotriazole hydrate and 1.96 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After stirring for 20 hours at 20° C., the reaction mixture is washed with 100 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is recrystallized in ethyl ether and the crystals are drained and then dried under reduced pressure (2.7 kPa). 3.1 g of (3aRS,7RS,7aSR)-7-hydroxy-7-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone are obtained, in the form of a white solid melting at 184° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19](=[O:21])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:17][CH2:18]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Isopropylamine (925 μL, 10.86 mmol) was added to a stirred solution of trans 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.32 g, 5.43 mmol), HATU (2.06 g, 5.43 mmol) and diisopropylethylamine (2.79 mL, 16.3 mmol) in DMF (50 ml). The resulting mixture was stirred at ambient temperature for 72 hours. The solvent was evaporated under vacuum and the residues diluted with water and extracted into DCM. The combined organic extracts were washed with 1M sodium hydroxide, water and brine, dried with magnesium sulfate and concentrated under vacuum affording 1.37 g (89%) of trans (4-isopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. LCMS (Method B, ESI): RT=3.07 min, m+H+ MeCN=326.3; 1H NMR (400 MHz, DMSO) δ: 7.50 (d; 1H); 6.66 (d; 1H); 3.78 (m; 1H); 3.13 (m; 1H); 1.94 (m; 1H); 1.78 (d; 2H); 1.66 (d; 2H); 1.37 (s; 9H); 1.31 (m; 2H); 1.11 (m; 2H); 1.01 (d; 6H).