Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([O-])(=[O:25])=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Na+].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:39]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:42])([CH3:41])[CH3:40].CCN(CC)CC>C1COCC1.C(Cl)Cl>[C:39]([N:43]1[CH2:48][CH2:47][N:46]([S:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[N:18]=[C:17]4[C:16]=3[CH:19]=2)(=[O:24])=[O:25])[CH2:45][CH2:44]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)[O-])ccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN(C(C)(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.7 %

Procedure:
To a suspension of sodium 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonate (0.34 mmol) in THF (10 mL) was added oxalyl chloride (143 μL, 1.69 mmol) and the resulting mixture stirred at RT for 10 min then cooled to 0° C. before DMF (126 μL, 1.69 mmol) was added. The resulting mixture was stirred for 3 h then azeotroped with toluene. The resulting residue was suspended in DCM (15 mL) and added to a solution of tert-butylpiperazine (96 mg, 0.68 mmol) and NEt3 (157 μL, 1.13 mmol) in DCM (10 mL) at RT The resulting mixture was stirred for 1 h then quenched with a saturated aqueous NaHCO3 solution. The organic phase was washed with H2O and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 3-20% 2M NH3/MeOH in EtOAc then C18, gradient 25-45% MeOH in H2O). The resulting residue was partitioned between DCM and a saturated aqueous NaHCO3 solution, the organic phase dried (Na2SO4) and concentrated in vacuo affording 121 (25 mg, 22%). LCMS: RT 2.93 [M+H]+ 500.3. 1H NMR (DMSO, 400 MHz): δ 8.78 (1H, d, J=2.41 Hz), 8.00 (1H, s), 7.94 (1H, s), 7.62 (1H, dd, J=8.62, 2.42 Hz), 7.28 (1H, d, J=8.62 Hz), 5.74-5.74 (1H, m), 4.64-4.60 (4H, m), 2.92-2.85 (4H, m), 2.59-2.53 (4H, m), 1.49 (6H, d, J=6.62 Hz), 0.93 (9H, s)
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:16][S:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)(=[O:13])=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Product: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Yield: 87 %

Procedure:
5-Phenylmethanesulfonyl-1,3-dihydro-indol-2-one was prepared according to the method described by Jiong Jack Chen et al. (Organic Process Research and Development, 2003, 7, 313-317) from 1 g (4.32 mmol) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride and 0.51 mL (4.32 mmol) of bromomethyl-benzene. After filtration and washing with acetone, 1.08 g (87%) of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one is obtained in the form of a white solid.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([NH:36][CH2:37][CH2:38]O)[CH2:33][CH2:34][CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:38][CH2:37][NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:38][CH2:37][NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCNCCO
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCCCNCCOB(c1ccccc1)C(OC(B(OCCNCCCC)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (35 mg) was obtained by allowing 40.6 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 23 mg of N-n-butylethanolamine to act in 1 mL of ethanol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:21].[C:22]1([PH+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br-:21].[C:35]1([P+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ccccc1OCCCCCc1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: c1ccc(CCCCCOc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 18.7 g (69.16 mmol) of [2-(5-phenylpentyloxy)phenyl]methanol in 120 ml of acetonitrile is mixed with 22.55 g (65.71 mmol) of triphenylphosphonium bromide and heated under reflux for 3 hours. The reaction solution is then concentrated to dryness. 36.6 g (61.45 mmol, 83% of theory) of crystalline product are obtained and are reacted without further purification.
Reaction SMILES: Cl.C[CH:3](N(C)C)[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(NC1C=CC=CC=1)C>[OH-].[Na+]>[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:11])[CH3:3]
Reactant: CC(C(O)c1ccccc1)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCNc1ccccc1
Product: CC(=O)c1ccccc1

Procedure:
The aqueous layer and the 10% hydrochloric acid washings were joined and the joined solution was mixed with a 10% sodium hydroxide solution (30 ml) to adjust the pH to about 11 and extracted with ethyl acetate (50 ml×3). The extract was washed with a saturated saline solution (50 ml×3), dried and then ethyl acetate was distilled off to obtain a mixture of N-methylephedrine and N-ethylaniline. Yield: 2.4 g (100%). Said two substances can be recovered, separately by distilling the mixture under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:7]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1cc(Br)cnc1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
To a solution of 5-bromo-2-pyrimidinone (5.3 g, 30 mmol) in N,N-dimethylformamide (50 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (8.5 mL, 39 mmol) and cesium carbonate (12 g, 36 mmol). The mixture was stirred at 25° C. for 3 days, then poured into aq. NaHCO3 (500 mL) and extracted with 50% EtOAc/hexane (3×200 mL). The combined extracts were washed with H2O (3×200 mL) and brine (200 mL) and then dried (Na2SO4) and concentrated to afford a brown solid. Recrystallization from EtOAc/hexane afforded the title compound as an off-white crystalline solid (6.0 g, 59% yield). MS (ESI, pos. ion.) m/z: 333 (MH+). Calc'd exact mass for C12H21BrN2O2Si: 333. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.08 (s, 6 H), 0.80 (s, 9 H), 3.81 (t, J=5.0 Hz, 2 H), 3.96 (t, J=5.0 Hz, 2 H), 8.40 (d, J=3.3 Hz, 1 H), 8.63 (d, J=3.3 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[NH:4][C:5](=[NH:8])[S:6][CH3:7].[C:11]([N:15]=[C:16]=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:1][N:2]([CH3:10])[C:3]([N:4]=[C:5]([S:6][CH3:7])[NH:8][C:16]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:9]
Reactant: CC(C)(C)N=C=O
Reactant: CSC(=N)NC(=O)N(C)C
Solvent: ClCCl
Product: CSC(=NC(=O)N(C)C)NC(=O)NC(C)(C)C
Reaction time: 8 h

Procedure:
A mixture of 7 parts methyl 4,4-dimethylthioallophanimidate, 8 parts of t-butylisocyanate and 50 ml methylene chloride is refluxed for 2 hours. After standing overnight at room temperature, the solution is evaporated under vacuum to give a viscous oil, which solidified after trituration with petroleum-ether. Recrystallization from petroleum-ether gives methyl N-dimethylcarbamoyl-4-tert-butylthioallophanimidate, (a compound of formula I), m.p. 74°-78° C.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:33]([O:40][CH:41]1[CH:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:44]([CH2:63][O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[O:43][C:42]1=[O:72])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>C1COCC1>[S:28]1[C:24]([CH2:23][C:15]2[CH:14]=[C:13]([C:42]3([OH:72])[C@H:41]([O:40][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C@@H:46]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C@@H:45]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C@@H:44]([CH2:63][O:64][CH2:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[O:43]3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]1=2
Reactant: Brc1cc(Cc2cc3ccccc3s2)cc2ccccc12
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cc(Cc3cc4ccccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, an n-butyllithium hexane solution (1.6 M, 1.58 ml, 2.53 mmol) was added dropwise to a solution of 2-(4-bromonaphthalen-2-ylmethyl)-benzo[b]thiophene (0.81 g, 2.29 mmol) in anhydrous THF (15 ml) at −78° C. over five minutes. The reaction mixture was stirred at −78° C. for 5 minutes, and then a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran-2-one (1.36 g, 2.52 mmol) in anhydrous THF (10 ml) was added dropwise thereto at −78° C. and the reaction solution was stirred at −78° C. for 2 hours. To the obtained reaction mixture was added a saturated ammonium chloride aqueous solution and the mixture was extracted with diethyl ether and the organic layer was washed with a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel flash column chromatography [n-hexane:ethyl acetate (10:1)] to obtain the title compound (1.4 g, 75%).
Reaction SMILES: F[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:12]1([OH:16])[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:16][C:2]2[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: OC1CCC1
Reactant: Cc1cc(C(=O)O)cnc1F
Product: Cc1cc(C(=O)O)cnc1OC1CCC1
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (1.18 g, white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and cyclobutanol (837 mg, 11.6 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2(C3C=CN=CC=3)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][C:26]([S:29](N)=[O:30])([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4](/[C:8](/[C:16]2[CH:15]=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=2[C:10]#[N:18])=[N:9]\[S:29]([C:26]([CH3:28])([CH3:27])[CH3:25])=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(N)=O
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cc(Cl)ccc21
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cc(Cl)ccc1C#N
Temperature: 50 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
Titanium(IV) ethoxide (1M in tetrahydrofuran, 7.07 mL, 7.07 mmol) was added to 2-(3-bromobenzoyl)-4-chlorobenzonitrile (Scheme #18 R, 1.03 g, 3.21 mmol) at room temperature under argon atmosphere. 2-Methyl-2-propanesulfinamide (0.428 g, 3.53 mmol) was added 2 minutes later. The reaction mixture was refluxed overnight and then stirred at 50° C. for 24 h. The mixture was cooled to ambient temperature and diluted with methanol (7 mL). Saturated aqueous sodium bicarbonate was added and the mixture was diluted with ethyl acetate. The gelatinous precipitate formed was filtered off through a pad of magnesium sulfate (top) and diatomaceous earth (bottom). The filtrate was concentrated and the residue was purified by flash chromatography using ethyl acetate in heptane (0-40%) affording 0.956 g (70% yield) of the title compound. 1H NMR (DMSO-d6) δ 8.01 (d, J=6.53 Hz, 1 H), 7.95-7.75 (m, 3 H), 7.71 (s, 1 H), 7.52-7.44 (m, 2 H), 1.28 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:22])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:4]([Cl:23])[N:3]=1.[CH3:24]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:24])[C:7](=[O:22])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:4]([Cl:23])[N:3]=1
Reactant: COc1ccc(Cn2c(=O)[nH]c3c(Cl)nc(N)nc32)cc1OC
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(Cn2c(=O)n(C)c3c(Cl)nc(N)nc32)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of 2-amino-6-chloro-9-[(3,4-dimethoxyphenyl)methyl]-7H-purin-8-one (8.8 g, 26.21 mmol), DMF (90 ml), potassium carbonate (5.4 g, 39.31 mmol) and methyl iodide (1.96 ml, 31.45 mmol) stirred at 25° C. for 3 hours. Reaction mixture was cooled to 0° C. Water was added and solid obtained was filtered off to obtain 2-amino-6-chloro-9-[(3,4-dimethoxyphenyl)methyl]-7-methyl-purin-8-one (9.0 g, 98%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:25][CH2:26][O:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:9]1[C:10]([N+:22]([O-:24])=[O:23])=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH:18]=1)[C:14]([O:16]C)=[O:15])(=[O:4])=[O:3].[OH-].[K+]>O1CCOCC1>[CH3:31][S:28]([O:27][CH2:26][CH2:25][N:8]([CH2:7][CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:9]1[C:10]([N+:22]([O-:24])=[O:23])=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH:18]=1)[C:14]([OH:16])=[O:15])(=[O:29])=[O:30]
Reactant: COC(=O)c1cc(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Hydrolysis of 7 (3.0 g, 6.18 mmol) with 3 N KOH (40 mL) in dioxane (200 mL) at room temperature for 15 min followed by acidification with 1N HCl and extraction with EtOAc gave a quantitative yield of 5-(bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,4-dinitrobenzoic acid (8), mp 200-210° C., which was used for the next step without further purification;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O)(C(F)(F)F)=O>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1C1NCCc2c1[nH]c1ccccc21
Yield: 69 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 2-chlorobenzaldehyde (0.7 mL, 1.0 equiv.) and TFA (1.0 mL, 2 equiv.) to give the title compound (1.2 g, 69%). 1H NMR (CDCl3) δ 7.6 (s, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 6.9-7.2 (m, 6H), 5.6 (s, 1H), 3.2-3.0 (m, 2H), 2.9-2.7 (m, 2H), 2.4 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.O[C:26]1[C:35]([OH:36])=[CH:34][C:33]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=3)[O:36][C:35]3[CH:34]=[C:33]([S:37]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)(=[O:39])=[O:38])[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[C:26]=3[O:8]2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc(O)c1O
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc2c1OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)O2

Procedure:
4,4′-Dimethoxybenzophenone (225 mg, 0.93 mmol, 1.5 eq.), oxalyl chloride (944 mg, 7.44 mmol, 8 eq.) and methyl 2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzoate (200 mg, 0.62 mmol, 1 eq.) were reacted according to GP2.2. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 20:1→9:1) to yield the title compound as a colorless solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:12]N)[CH:4]=1.O=[C:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]1>C(O)(=O)C.CCOC(C)=O>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:20]1[CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:15]=1[NH:12]2
Reactant: NNc1cc(Br)ccc1C(=O)O
Reactant: CCOC(=O)C1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)ccc(Br)c23)C1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
Step 2 A stirred suspension of 4-bromo-2-hydrazinylbenzoic acid hydrochloric acid salt (16.35 g, 58.1 mmol) in acetic acid (171 mL) was treated with ethyl 3-oxocyclohexanecarboxylate (9.88 g, 58.1 mmol) at rt. The mixture was stirred at reflux for 2.5 h, then was cooled to rt and concentrated to afford a brown solid. This was suspended in EtOAc (20 mL) and the precipitate was collected by filtration, washed with EtOAc and air dried to provide 5-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (11.46 g). The filtrate was concentrated and the residue was resuspended in EtOAc, the precipitate collected by filtration and dried to provide additional product (0.82 g) for a total of 12.28 g (58%). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br. s., 1H) 11.06 (s, 1H) 7.50 (d, J=8.13 Hz, 1H) 7.19 (d, J=8.13 Hz, 1H) 4.07-4.15 (m, 2H) 3.08-3.19 (m, 1H) 2.99-3.08 (m, 1H) 2.89-2.99 (m, 2H) 2.79-2.89 (m, 1H) 2.09-2.22 (m, 1H) 1.75-1.89 (m, 1H) 1.20 (t, J=7.14 Hz, 3H). Mass spectrum m/z 366.0, 368.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:38])=[CH:32][CH:31]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccc(F)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (43.1 mg, 0.102 mmol) and 4-fluorophenyl isocyanate (Aldrich, 71.0 mg, 0.512 mmol) in CH2Cl2 (5 mL) was stirred at rt for 24 hrs. The reaction mixture was then concentrated and purified by flash column to give (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-fluoro-phenyl)-amide (45.6 mg, 79.8%). HRMS (ES+) m/z Calcd for C29H26Cl2F3N3O+H [(M+H)+]: 560.1478; Found: 560.1479.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1)C=C.CN(C)[C:20]1[CH:25]=CC=C[CH:21]=1>>[CH2:25]([C:10]1[CH:9]=[C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:20]=[CH2:21]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C2=NNC(=O)CC2)cc1
Product: C=CCc1cc(C2=NNC(=O)CC2)ccc1O
Yield: 87 %

Procedure:
A mixture of 6-(4-allyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (81.8 g, 0.36 mole) and N,N-dimethylaniline (200 ml) was heated under reflux in an atmosphere of nitrogen for 6 hours, then allowed to cool overnight. The collected product was well washed with ether to give 6-(3-allyl-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (71.5 g, 87%, m.p. 240°-244°C). Recrystallisation from 2-methoxyethanol gave the pure material of m.p. 242°-244°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:36])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1>ClCCl.CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:36][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1CCC(OC)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC(OC)CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 186 mg (0.66 mmol) of 3-methoxy-4-[2-(4-methoxypiperidin-1-yl)ethoxy]phenylamine. Yield: 20 mg (7% of theory); melting point: 195° C.-197° C.; C25H26ClF3N2O4 (M=510.93); calc.: molecular ion peak (M+H)+: 511/513 (Cl); found: molecular ion peak (M+H)+: (M+H)+: 511/513 (Cl); Rf value: 0.3 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1B(O)O)=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([C:7]2[CH:6]=[CH:5][S:4][C:3]=2[CH:1]=[O:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccccc1
Reactant: O=Cc1sccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: O=Cc1sccc1-c1ccccc1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
2-Formylthiophen-3-boronic acid (4) (0.89 g, 5.7 mmol) dissolved in 96% ethanol (15 ml) was added dropwise to a mixture of 2-bromobenzene (0.66 ml, 6.2 mmol) in benzene (12 ml), (Ph3P)4Pd (197 mg, 0.15 mmol) and an aqueous solution of 2M Na2CO3 (6.3 ml). The reaction mixture was then refluxed for 6 hrs. Then the mixture was cooled to room temperature, the solvent was partially removed under reduced pressure and the resulting mixture was extracted with ethyl ether (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was chromatographed using 95/5 petroleum ether/ethyl acetate, thus giving the derivative (5) (0.575 g, [lacuna] mmol, 53% yield).