Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:34])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:33])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:32])[C@H:22]([CH3:31])[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:34])=[O:8])=[O:33])=[O:32])[CH3:31])=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 99.8 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-L-prolyl-L-proline benzylester (5.0 g, 10.6 m mole) was dissolved in methanol (100 ml) and hydrogen gas was passed through the solution in the presence of the palladium carbon as a catalyst for 3 hours. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. Thus obtained residue was dissolved in water and the solution was freeze-dried to give N-t-butyloxycarbonyl-L-alanyl-L-prolyl-L-proline (4.04 g).
Reaction SMILES: CS(OCCCOC1C=CC=C(C2N(C3C=CC=C(Cl)C=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=1)(=O)=O.N.[CH:37]([OH:39])=[O:38].C(O)=O.[Cl:43][C:44]1[CH:45]=[C:46]([N:50]2[C:54]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([O:61][CH2:62][CH2:63][CH2:64][N:65](C)C)[CH:56]=3)=[CH:53][C:52]([C:68]([N:70]3[CH2:74][C:73](=[O:75])[NH:72][CH2:71]3)=[O:69])=[N:51]2)[CH:47]=[CH:48][CH:49]=1>CO>[CH:37]([OH:39])=[O:38].[NH2:65][CH2:64][CH2:63][CH2:62][O:61][C:57]1[CH:56]=[C:55]([C:54]2[N:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([Cl:43])[CH:45]=3)[N:51]=[C:52]([C:68]([N:70]3[CH2:74][C:73](=[O:75])[NH:72][CH2:71]3)=[O:69])[CH:53]=2)[CH:60]=[CH:59][CH:58]=1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: N
Solvent: O=CO
Solvent: CO
Product: NCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and a 7N solution of ammonia in methanol with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 29. 10 mg (10% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:24]([OH:29])(=[O:28])[C:25]([CH3:27])=[CH2:26].N(C(C)(CC)C([O-])=O)=NC(C)(CC)[C:33]([O-])=[O:34]>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:11]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:24]([OH:29])(=[O:28])[C:25]([CH3:27])=[CH2:26].[C:1]([O:6][CH:7]([CH3:10])[CH2:8][O:34][CH3:33])(=[O:5])[CH3:2]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OC(C)(C)C
Agent: C=C(C)C(=O)OCc1ccccc1
Solvent: CC(=O)CC(C)C
Solvent: CCCCCCC
Product: COCC(C)OC(C)=O
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 51.2 g (0.36 mol) of tert-butyl methacrylate, 21.1 g (0.12 mol) of benzyl methacrylate, 10.3 g (0.12 mol) of methacrylic acid and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in propylene glycol monomethyl ether acetate, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A′1-8 (tert-butyl methacrylate/benzyl methacrylate/methacrylic acid) as a propylene glycol monomethyl ether acetate solution.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:21])([C:16]1[N:17]=[CH:18][S:19][CH:20]=1)[CH2:12]2)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[S:19]1[CH:20]=[C:16]([C:11]2([OH:21])[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)[N:17]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cscn1)C2
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2cscn2)CC2CCC(C1)N2
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
3-Hydroxy-3-thiazol-4-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.22 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 2.5 mL). The mixture was stirred for 0.5 hours at 45° C. and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound (0.20 g). LCMS m/z 211.1 [M+H]+. R.T.=0.35 min. (Analytical Method 3).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5ccc(NC6CC6)nn5)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a khaki solid. Mp: 130-131° C.; 1H NMR (300 MHz, CDCl3) δ: 8.11-8.13 (1H, d, J=6.0 Hz), 7.86 (1H, s), 7.64 (2H, m), 7.42-7.45 (1H, d, J=9.0 Hz), 7.39-7.42 (1H, d, J=9.0 Hz), 7.22 (1H, s), 7.01-7.04 (1H, d, J=9.0 Hz), 6.00 (1H, s), 3.61 (2H, s), 2.60 (1H, m), 2.44 (8H, brs), 2.27 (3H, s), 0.87-0.89 (2H, m), 0.65 (2H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H29ClN7: 498.2167. found: 498.2150.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:25]2[CH:26]=[C:21]([C:19]([C:18]3[CH:27]=[CH:28][CH:29]=[CH:16][CH:17]=3)=[O:20])[CH:22]=[CH:23][CH:24]=2)=[CH:9][CH:8]=1
Reactant: OCc1ccc(CC2OCCO2)cc1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cccc(OCc2ccc(CC3OCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
To a cooled (0° C.) solution of (4-((1,3-dioxolan-2-yl)methyl)phenyl)methanol (0.45 g, 2.317 mmol), 3-hydroxybenzophenone (0.551 g, 2.78 mmol) and triphenylphosphine (0.729 g, 2.78 mmol) in anhydrous THF, di-iso-propylazodicarboxylate (1.027 mL, 2.78 mmol) was added dropwise. The reaction mixture was allowed to warm to RT and stirred at this temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous potassium carbonate, brine and dried (magnesium sulfate). The suspension was filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 25% ethyl acetate in iso-hexane to afford the title compound (1.022 g, >100%).
Reaction SMILES: C(OC1C=CC(C(Cl)=O)=CC=1)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[F:35].[CH2:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH3:37]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH3:37].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([O:38][CH2:36][CH3:37])=[CH:40][CH:41]=2)=[S:49])=[CH:30][C:29]=1[F:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CCOc1ccc(C(=O)Cl)cc1
Agent: CCOc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-Ethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-ethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-ethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 92%). Mass spectrometry value (ESI-MS, m/z): 554 (M++1)
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[O:15]1[CH2:20]CC(=O)[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:17][CH2:16][O:15][CH2:20][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=C1CCOCC1
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)COCC2
Yield: 52 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4 mmol), tetrahydro-4H-pyran-4-one (0.4 g, 4 mmol) and ammonia solution in methanol (2.0M, 40 mL) was refluxed for 4 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatocraphed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (O.376 g, 52% yield).
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[C@H:26]([CH3:42])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43]COC(C)=O>[Pd]>[CH2:1]([C@@H:8]([CH2:24][CH2:25][C@H:26]([CH2:42][CH3:43])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CC[C@@H](CC[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (2S,5S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-methylhex-3-ene-1,6-dione (250 mg, 0.431 mmol) in EtOAc (5 mL) was added 10% Pd/C (80 mg, 0.075 mmol). The reaction mixture was purged with nitrogen and stirred under an atmosphere of hydrogen (balloon) overnight. The reaction mixture was filtered through CELITE® and concentrated to afford (2R,5S)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-ethylhexane-1,6-dione (221 mg, 0.379 mmol, 88% yield), which was used without further purification. Anal. Calcd. for C35H38N2O6 m/z 582.3. found 579.2 (M−); 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.31 (m, 5H), 7.27-7.21 (m, 7H), 7.04-7.02 (m, 3H), 4.68-4.66 (m, 2H), 4.19-4.11 (m, 4H), 4.04 (m, 1H), 3.66 (bs, 1H), 3.32 (m, 1H), 3.05-3.0 (m, 2H), 2.80 (m, 1H), 2.68 (m, 1H), 2.36 (m, 1H), 1.75-1.68 (m, 4H) 1.25 (t, J=7.2 Hz, 2H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([NH:15][C:16]1[S:17][C:18]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19][N:20]=1)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:29][O-].[Na+].CBr>CO.O>[C:1]([NH:11][CH2:12][C:13]([N:15]=[C:16]1[N:20]([CH3:29])[N:19]=[C:18]([S:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:17]1)=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C[O-]
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1nnc(SCc2ccccc2)s1
Agent: CBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1nc(SCc2ccccc2)sc1=NC(=O)CNC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A solution of the product from Example VIII (ca 30 gm, 0.1 mole) in methanol (200 ml)m containing sodium methoxide (from 2.5 g sodium, 0.11 mole) is warmed in a flask fitted with a Dry Ice condenser, stirred 3 hr., then cooled to 5° C. Methyl bromide gas was then passed through the reaction (0.15 mole) and the solution stirred overnight at room temperature. The solution is diluted with water (200 ml) to give a sticky solid, ca25 gm. this is slurried with cold concentrated sodium hydroxide solution to remove starting material Yield 20 gm, 40%, recrystallized from ethanol, 15 gm, m.p. 92° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH2:12]([NH2:14])[CH3:13].O1CCCC1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:14][CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCNC1=C(C(=O)OCC)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with a 2.0 M solution of ethylamine in tetrahydrofuran (9.6 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-ethylamino-cyclopent-1-enecarboxylic acid ethyl ester (1.52 g, 8.30 mmol, 43.2%), as a light yellow oil. LC-MS (ESI) calcd for C10H17NO2 183.13, found 184.1 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][O:17][C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[OH:42][C:25]([CH3:41])([CH3:24])[CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:20])([CH3:21])[CH2:18][O:17][C:16]5=[O:22])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH:29]=[N:28]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)COC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(N4C(=O)OCC4(C)C)nc2-3)cn1
Yield: 22 %

Procedure:
3-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-yl)-4,4-dimethyloxazolidin-2-one was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol to give 356. Yield 22%. MS(ESI+): 455.1. 1H NMR (400 MHz, DMSO) δ 8.16 (d, J=8.3, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.37 (dd, J=8.3, 1.8, 1H), 7.24 (d, J=1.8, 1H), 4.71 (s, 1H), 4.32 (d, J=6.9, 4H), 4.05-4.00 (m, 2H), 3.25 (t, J=5.0, 2H), 1.76 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [Br: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([OH:13])[CH3:12].[CH3:14]C(C)([O-])C.[K+].COS(C1C=CC(C)=CC=1)(=O)=O.[Cl-].[NH4+]>CN(C=O)C>[Br: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:13][CH3:14])[CH3:12]
Reactant: CC(C)(C)[O-]
Reactant: CC1(O)C(=O)Nc2ccc(Br)cc21
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1(C)C(=O)Nc2ccc(Br)cc21
Temperature: 0 °C
Yield: 53.7 %

Procedure:
5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.0 g, 4.1 mmol) was dissolved in dry DMF (15 cm3) cooled to 0° C. and treated with potassium tert-butoxide (1M in THF, 4.5 cm3, 4.5 mmol). After 15 min. methyl-p-toluenesulfonate (0.93 g, 5 mmol) was added and the mixture was allowed to warm up-to room temperature. After 2 h the mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (×2), then the combined organic layers were washed with water, sodium hydroxide (1N, ×2), water (×3), dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc:hexane, gradient elution) to afford 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.56 g, 2.2 mmol, 53%): 1H NMR (CDCl3) δ 1.59 (s, 3H), 3.18 (s, 3H), 6.73 (d, 1H, J=8.2 Hz), 7.45 (dd, 1H, J=8.2, 2 Hz), 7.52 (d, 1H, J=2 Hz); MS (EI) m/z 225 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14]C)=[O:13])[CH:8]=[C:7]2[OH:16].CO.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[C:7]2[OH:16]
Reactant: COC(=O)c1cc(O)c2ccc(OC)c(Cl)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(O)cc(C(=O)O)nc2c1Cl
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylate 214 (36.5 g, 0.145 mol) in a mixture of 1:1 of MeOH:THF (160 mL total) was added a solution of LiOH (30.5 g, 0.725 mol) in H20 (80 mL). The mixture was stirred at room temperature for an hour when LCMS analysis showed complete conversion to the carboxylic acid. The reaction was worked up by removal of the volatiles and adjusting the pH of the solution to 6 using aqueous 6N HCl. The resulted gummy residue was filtered and dried on the lyophilizer for 2 days to provide 34.4 g (99.6%) of compound 215 as a white solid. EI MS (m/z) 253.9 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:34][P:35]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])=[O:36])(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]([CH2:34][P:35](=[O:36])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cc(Cl)cc(Cl)c1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN(c1ccc2[nH]ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.56 g 3,5-dichloro-N-(1H-indol-5-yl)-phenylsulphonamide are dissolved in 25 ml dimethylformamide. To this, 3.11 g potassium carbonate and 2.93 ml diethoxy-phosphorylmethyl trifluoro-methanesulphonate are added dropwise. The mixture is stirred overnight at ambient temperature, divided between water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed twice with water and once with saturated sodium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo, the residue is dissolved in hot ethyl acetate and after cooling to ambient temperature the precipitated solid is suction filtered. Further product is obtained by freeing the mother liquor in vacuo from the volatile constituents and chromatographing the residue on silica gel (cyclohexane/ethyl acetate 50:50 to 25:75).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:30][CH2:31][CH2:32][CH2:33][Cl:34].O>CN(C)C=O.O1CCCC1>[Cl:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: ClCCCCBr
Reactant: CCOC(=O)Cc1cccc(-c2cccnc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCl)c1cccc(-c2cccnc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 0.363 g (1.5 mmol) of ethyl m-(3-pyridyl)phenylacetate in 5.4 mL dry dimethylformamide at 5° C. is added 1.56 mL of a 1M solution of sodium hexamethyldisilazide in tetrahydrofuran. The organic layer is evaporated to dryness and resulting orange colored solution is stirred for 10 minutes and 0.54 mL (4.7 mmol) 1-bromo-4-chlorobutane is added rapidly. The reaction is stirred at 5° C. for 2 hours and then poured into water and extracted thrice with ether. The organic layer is evaporated to dryness and the resulting oil is purified by flash chromatography using 1:1 ether and hexane to obtain ethyl 6-chloro-2-[m-(3-pyridyl)phenyl]hexanoate; IR (CH2Cl2): 1728, 1278, 1184, 1165, 1023 cm-1.