Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][C:22]1[N:17]2[CH:18]([CH3:37])[C:19](=[O:36])[N:20](COCC[Si](C)(C)C)[N:21]=1)(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[NH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][C:22]1[N:17]2[CH:18]([CH3:37])[C:19](=[O:36])[NH:20][N:21]=1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(N4CCCC4CNC(=O)OC(C)(C)C)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3ccc(N4CCCC4CN)cc3N21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of crude {1-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-pyrrolidin-2-ylmethyl}-carbamic acid tert-butyl ester (0.117 mol) in DCM (2 mL) and TFA (1 mL) was stirred for 1 h at ambient temperature. The solvent was removed in vacuo and the residue was re-dissolved in MeOH (2 mL) and aqueous ammonium hydroxide (25%, 0.5 mL). The mixture was stirred for 2 h then purified by preparative HPLC (Table 3, Method 20) to give 6-(2-aminomethyl-pyrrolidin-1-yl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as white solid (0.0068 g, 13% for 2 steps). LC/MS (Table 1, Method 4) Rt=1.111 min; MS m/z: 316 [M+H]+
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]2([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:15][CH2:14]2)C=CC=CC=1.[ClH:21]>CO>[ClH:21].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:15]1
Reactant: c1ccc(CN2CCC[C@H]2C2(N3CCCC3)CC2)cc1
Agent: Cl
Solvent: CO
Product: C1CN[C@H](C2(N3CCCC3)CC2)C1
Yield: 99 %

Procedure:
(2S)-1-(Phenylmethyl)-2-[1-(1-pyrrolidinyl)cyclopropyl]pyrrolidine (1.083 g, 4.00 mmol) was dissolved in a mixture of MeOH (30 mL) and 1N HCl (8.8 mL), degassed and placed under argon. 10% Pd/C (325 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through a fiberglass filter, washing with MeOH. The filtrate was concentrated in vacuo to provide pure 1-{1-[(2S)-2-pyrrolidinyl]cyclopropyl}pyrrolidine hydrochloride (0.978 g, >99%). LCMS: (M+H)+: 181.2.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([NH:34][C@H:35]([C:38]([NH:40][C@H:41]([C:46]([NH:48][C@H:49]([C:62]([NH:64][C@H:65]([C:71]([NH:73][C@H:74]([C:79]([NH:81][C@H:82]([C:92]([NH:94][C@H:95]([C:100]([NH:102][C@H:103]([C:116]([NH:118][C@H:119]([C:141]([NH:143][C@H:144]([C:149]([O:151]C(C)(C)C)=[O:150])[CH2:145][C:146](=[O:148])[NH2:147])=[O:142])[CH2:120][S:121]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:117])[CH2:104][C:105]1[CH:110]=[CH:109][C:108]([O:111]C(C)(C)C)=[CH:107][CH:106]=1)=[O:101])[CH2:96][C:97](=[O:99])[NH2:98])=[O:93])[CH2:83][CH2:84][C:85](=[O:91])[O:86]C(C)(C)C)=[O:80])[CH2:75][CH:76]([CH3:78])[CH3:77])=[O:72])[CH2:66][CH2:67][C:68](=[O:70])[NH2:69])=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57]C(C)(C)C)=[CH:53][CH:52]=1)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:11][S:12]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].FC(C(O)=O)(F)F.O>C(S)C.FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([NH:34][C@H:35]([C:38]([NH:40][C@H:41]([C:46]([NH:48][C@H:49]([C:62]([NH:64][C@H:65]([C:71]([NH:73][C@H:74]([C:79]([NH:81][C@H:82]([C:92]([NH:94][C@H:95]([C:100]([NH:102][C@H:103]([C:116]([NH:118][C@H:119]([C:141]([NH:143][C@H:144]([C:149]([OH:151])=[O:150])[CH2:145][C:146](=[O:148])[NH2:147])=[O:142])[CH2:120][SH:121])=[O:117])[CH2:104][C:105]1[CH:106]=[CH:107][C:108]([OH:111])=[CH:109][CH:110]=1)=[O:101])[CH2:96][C:97](=[O:99])[NH2:98])=[O:93])[CH2:83][CH2:84][C:85](=[O:86])[OH:91])=[O:80])[CH2:75][CH:76]([CH3:77])[CH3:78])=[O:72])[CH2:66][CH2:67][C:68](=[O:70])[NH2:69])=[O:63])[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=1)=[O:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:11][SH:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCS
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.429 g (1.5 mmoles) of H-Ile-Cys(Trt)-Ser-Leu-Tyr(But)-Gln-Leu-Glu(OBut)-Asn-Tyr(But)-Cys(Trt)-Asn-OBut trifluoroacetate are dissolved in a mixture of 19 ml of ethylmercaptan and 19 ml of trifluoroacetic acid. The reaction mixture is stirred for 4 hours at room temperature and is then poured into 250 ml of water, while stirring. The precipitate is filtered off, washed with ether and dried. It is then triturated with ether, filtered off and dried. Yield 1.964 g. This substance is then deblocked once more as described above. Yield 1.6 g (61%). In total, a further 330 mg of substance was obtainable from the filtrates after extraction with ether and freeze-drying.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1S([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[O:31][CH2:30][CH2:29][N:28](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:27]2)=[CH:22][CH:21]=1)(=O)=O)([O-])=O.BrC1C=CC(S)=CC=1.Cl>CN(C)C=O>[NH:28]1[CH2:29][CH2:30][O:31][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([OH:19])=[CH:21][CH:22]=2)[CH2:27]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Oc1ccc(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Sc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: Oc1ccc(C2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
Potassium carbonate (0.88 g, 6.33 mmol) was added to a solution of 1.16 g (2.11 mmol) of the title compound produced in step (iii) of Reference Example 12 in N,N-dimethylformamide (8.5 ml), and the mixture was stirred at room temperature for 5 min. Next, 1.20 g (6.33 mmol) of 4-bromobenzenethiol was added thereto, and the mixture was stirred at room temperature for 3.5 hr. The reaction was stopped by adding 1 N hydrochloric acid, and the reaction solution was adjusted to pH=3. The aqueous layer was washed with ethyl acetate and was concentrated to dryness under the reduced pressure. Methanol was added to the residue, and the mixture was filtered, The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1, chloroform:methanol:28% aqueous ammonia=9:2:0.2) to give 240 mg (yield 63%) of the title compound.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([N:23]2[CH2:29][CH2:28][CH2:27][C@:26]([CH2:36][CH2:37][CH2:38][OH:39])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:25][C:24]2=[O:40])[CH3:22])=[CH:17][CH:16]=1.CC(O)C>CC(C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([N:23]2[CH2:29][CH2:28][CH2:27][C@:26]([CH2:36][CH2:37][C:38]([OH:3])=[O:39])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:25][C:24]2=[O:40])[CH3:22])=[CH:17][CH:16]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CCCO)(c2ccccc2)NC1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CCC(=O)O)(c2ccccc2)NC1=O
Temperature: 0 °C
Yield: 69 %

Procedure:
A stirred mixture of Jones reagent (0.25 mL) and acetone (2 mL) was cooled in an ice bath and a solution of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(3-hydroxypropyl)-4-phenyl-1,3-diazepan-2-one (45 mg, 0.11 mmol) in acetone (6 mL) was added dropwise over 10 min The mixture was stirred in the ice bath for 2 h and i-PrOH (2 mL) was added. The mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (100 mL), washed with water (15 mL) and brine (15 mL), and dried over Na2SO4. Removal of the solvent afforded crude 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-2-oxo-4-phenyl-1,3-diazepan-4-yl)propanoic acid (33 mg, 69%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)cc1Br
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 2 g (7.434 mmol) 2-bromo-4-trifluoromethyl-benzoic acid (CAS: 328-89-2) in 20 ml DMF under nitrogen at room temperature, was added 1.13 g (8.177 mmol) potassium carbonate and 557 ul (8.921 mmol) methyl iodide. The mixture was stirred overnight under nitrogen. The mixture was poured into water (300 ml). The aqueous layer was extracted with ethyl acetate (2×80 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 10%) to provide 1.75 g (83%) of the title compound as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:17][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([CH3:36])OS1(=O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[N:17]([CH:34]([CH3:36])[CH2:35][NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCC)cnc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCC)cnc2n1C(C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to Example 3, intermediate j) from 5-ethoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([CH3:25])[NH:22][CH2:21][CH2:20]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(F)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(F)cccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][OH:21])[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=[O:21])[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CO)c1)CC(F)F
Agent: O=[Mn]=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)CC(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
MnO2 (3.89 g, 40.2 mmol) was added to a sol. of (4-chloro-3-hydroxymethyl-benzyl)-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (2.71 g, 18.2 mmol) in CH3CN (85 mL) at rt. The mixture was stirred at rt for 4 h, and MnO2 (2.71 g, 18.2 mmol) was added again. The mixture was stirred overnight. The mixture was filtered over Celite, and the precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure to yield the crude title compound (2.80 g, quantitative yield) that was used further without purification. LC-MS: tR=1.03 min; ES+: not visible.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[NH:24]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:25]1[C:26]([NH:28][CH:29]1[CH:33]([O:34]CC2C=CC=CC=2)[O:32][C:31](=[O:42])[CH2:30]1)=[O:27].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.ClCCl>[C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:24]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:25]1[C:26]([NH:28][CH:29]([CH:33]=[O:34])[CH2:30][C:31]([OH:42])=[O:32])=[O:27])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C1CC(NC(=O)C2CCCCN2)C(OCc2ccccc2)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CCCCC1C(=O)NC(C=O)CC(=O)O)C(C)C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
N-Acetyl-tyrosinyl-valine (464 mg, 1.44 mmol) and N-Pipecolyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran (412 mg, 1.3 mmol) were dissolved in 5 ml each of dimethylformamide and dichloromethane and cooled to 0° C. To the cooled solution was added 1-hydroxybenzotriazole (HOBT; 210 mg, 1.56 mmol) followed by the addition of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC; 326 mg, 1.7 mmol). After stirring for 18 hours, the mixture was diluted with ethyl acetate and washed with water, 10% sodium hydrogen sulfate, 10% sodium bicarbonate, and water. The organic layer was concentrated to give a crude solid that was purified by flash chromatography (SiO2) eluting with 94:6:1 (dichloromethane:isopropanol: pyridine) to give 370 mg of the title compound.
Reaction SMILES: [F: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=[CH:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:43][OH:44]>[Cl-].[Na+].O.CN(C=O)C>[F: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=[CH:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:43][OH:44])=[O:26])=[O:18])=[CH:15][CH:14]=1
Reactant: NO
Reactant: O=C(O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
6-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid (396 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (189 mg, 46%) as a brown solid. LC-MS (m/z) 412 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([OH:12])[C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1.CS(O[C@H:18]([C@@H:20]1[CH2:24][C:23](=[O:25])[N:22]([C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])[CH2:21]1)[CH3:19])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]([O:12][C@@H:18]([C@H:20]2[CH2:21][N:22]([C@@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:25])[CH2:24]2)[CH3:19])[C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](OS(C)(=O)=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: Cn1cnc2cc(Br)cc(O)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1C[C@H]([C@@H](C)Oc2cc(Br)cc3ncn(C)c23)CC1=O
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-1-methyl-1H-benzo[d]imidazol-7-ol 2.56 (15 mg, 0.066 mmol) in DMF (2 mL) was added (S)-1-((R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-3-yl)ethyl methanesulfonate 1.17 (41 mg, 0.312 mmol) and Cs2CO3 (33 mg, 0.1 mmol) and the reaction mixture was heated at 90° C. for 1 h. The reaction mixture was then diluted with ethyl acetate, washed with water (3×), brine and dried over anhydrous magnesium sulfate. Filtration, followed by concentration gave (R)-4-((R)-1-(5-bromo-1-methyl-1H-benzo[d]imidazol-7-yloxy)ethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one 2.57, which was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](O)=O.[Br:8][C:9]1[CH:10]=[C:11]([NH:16][CH3:17])[C:12]([NH2:15])=[CH:13][CH:14]=1.O=P(Cl)(Cl)Cl>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:3]([C:2]([CH3:7])([CH3:6])[CH3:1])[N:16]([CH3:17])[C:11]=2[CH:10]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: CC(C)(C)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(C(C)(C)C)nc2ccc(Br)cc21
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To a stirred solution of 2,2-dimethylpropionic acid (304 mg) and 4-bromo-N2-methylbenzene-1,2-diamine (400 mg) was added POCl3 (5 ml), and the mixture was heated at reflux for 4 h. The mixture was then cooled to room temperature, and poured into ice-cold saturated NaHCO3 solution. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (200 mg) as a light orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1.[C:13](=O)([O:16]C)[O:14]C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:13]([CH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:16])=[O:14]
Reactant: COC(=O)OC
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(CC(=O)O)c1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A mixture of 4-methoxy-2-methylbenzoic acid (10 g, 60 mmol) and dimethyl carbonate (10 ml, 120 mmol) in THF (80 ml) is added dropwise to LDA (120 ml of 2M in heptane/THF/ethylbenzene) at −78° C. The cold bath is removed, and after 4 h, water (100 ml) is added, and the resulting mixture is stirred overnight. After removal of organic solvents, the residue is acidified with c-HCl to pH 2. The resulting solid is filtered, dissolved in 1N—NaOH (80 ml), and then washed with ether (2×30 ml). The aqueous layer is acidified with c-HCl and the resulting white solid is filtered to give 12 g of 2-carboxymethyl-4-methoxy-benzoic acid. 1H NMR (DMSO) 12.3 (br s, 1H), 7.88 (d, 1H), 6.91 (d, 1H), 6.88 (s, 1H), 3.90 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [C:1]([S:11]C1C=CC(F)=CC=1)([S:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=S.[H-].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:32])[CH2:29][C:30]#[N:31])=[CH:24][CH:23]=1.CN(C=O)C>C1C=CC=CC=1>[C:30]([CH:29]([C:28]([C:25]1[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=1)=[O:32])[C:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)=[S:11])#[N:31]
Reactant: Fc1ccc(SC(=S)Sc2ccc(F)cc2)cc1
Reactant: N#CCC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#CC(C(=O)c1ccc(F)cc1)C(=S)Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
Trithiocarbonate (0.644 g, 2.15 mmol) from step (i) was added to a stirred suspension of sodium hydride (0.165 g, 0.412 mmol) in benzene (2.0 mL). Then, 3-(4-fluorophenyl)-3-oxopropanenitrile (0.320 g, 1.96 mmol) was added as a solution in benzene (2.0 mL). The reaction mixture was stirred for 5 min then DMF (2.0 mL) was added slowly. After addition was complete the reaction mixture was heated to reflux for 30 min and then allowed to cool to ambient temperature before being partitioned between H2O and Et2O. The aqueous layer was separated and washed with two additional portions of Et2O, then acidified with aqueous 2 N HCl. The acidic aqueous layer was then extracted with two portions of EtOAc, which were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with a gradient of 25-100% EtOAc/hexanes to afford the product as a yellow solid (0.20 g, 0.60 mmol, 31% yield). MS (M-H)− 332.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH2:7][C:6]=2[CH:11]=1.[NH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([NH2:12])=[O:9])[C:5]2[O:9][C:8](=[O:10])[CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:11]=3)[C:6]=2[CH:11]=1
Reactant: N
Reactant: O=C1Cc2cc(Cl)ccc2O1
Product: NC(=O)Cc1cc(Cl)cc2c1OC(=O)C2c1ccccc1

Procedure:
This compound was prepared according to the process described in Example 6, but using 5-chloro-2,3-dihydro-2-benzofuranone and ammonia solution in Stage A.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[CH3:26]I.Cl>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:26]
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (0.351 gm., 0.001 mole) in dimethylformamide (7 ml.) is cooled in an ice bath then treated with sodium hydride (0.084 g. of a 57% oil dispersion, 0.002 moles) and stirred for two hours. Methyl iodide (1 ml.) is added and the reaction mixture is stirred at 25° C. for two hours, poured into ice water, and acidified with dilute aqueous hydrochloric acid affording (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 168°-169° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8](=[O:21])[CH2:9][CH2:10][CH2:11][C:12]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[CH3:20][C:19]1[C:14]([CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[OH:21])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccnc1C(=O)CCCC(=O)c1ncccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccnc1C(O)CCCC(O)c1ncccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of 1,5-bis-(3-methyl-pyridin-2-yl)-pentane-1,5-dione (340 mg, 1.20 mmol) mmol) in MeOH (15 mL) was added NaBH4 (100 mg, 2.65 mmol) and the mixture was stirred at room temperature for 2 h. MeOH was removed in vacuo, water (25 mL) was added to the residue and the mixture was extracted with CH2Cl2 (3 times 25 mL). The organic extracts were dried over mgSO4 and concentrated to give 365 mg (100%) of 1,5-bis-(3-methyl-pyridin-2-yl)-pentane-1,5-diol as a white foam. 1H NMR(CDCl3): δ 1.52-1.81 (m, 6H), 2.33 (s, 6H), 4.69 (dd, 2H, J=7.5, 4.5 Hz), 4.79-4.86 (m, 2H), 7.09-7.14 (m, 2H), 7.43-7.45 (m, 2H), 8.36-8.39 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25]Cl)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:27][O-:28].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:28][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1
Reactant: C[O-]
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: [Na+]
Solvent: CO
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Yield: 78 %

Procedure:
The mixture of 5-bromo-3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (23 mg, 0.050 mmol), 0.1 M NaOMe (1 ml) in methanol (1 mL) was refluxed overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (18.0 mg, 78%).