Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH2]([O-])=O.[Na+].[OH2:5].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@@:14]2([CH3:39])[C:18](=[O:19])[N:17]([CH2:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C:16](=[O:31])[N:15]2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:9]=1)#N>[Ni].N1C=CC=CC=1.C(O)(=O)C.O>[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C@@:14]2([CH3:39])[C:18](=[O:19])[N:17]([CH2:20][C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[C:16](=[O:31])[N:15]2[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: O
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: C[C@]1(c2ccc(C=O)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 60 °C
Yield: 79 %

Procedure:
24.3 g of sodium hypophosphite×H2O and 4.02 g of Raney nickel were added to a solution of 6.08 g (13.42 mmol) of 8.1 in 200 ml of pyridine/acetic acid/water (2:1:1) at 0° C. and the reaction mixture was heated at 60° C. for 8 h. After cooling to room temperature and filtration, the reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and the ethyl acetate phase was extracted 2× with water, 2× with 10% strength citric acid solution, 2× with saturated NaHCO3 solution and with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and, after filtration, the solvent was removed in vacuo. 4.82 g (79%) of 8.2 were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C=O)C.N1C=CC=CC=1>[C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:20]2[N:19]=[CH:18][C:17]([NH:16][C:14]([C:12]3[O:13][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:10][N:11]=3)=[O:15])=[CH:22][CH:21]=2)[CH2:24][CH2:25]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 18 h
Yield: 68.4 %

Procedure:
5-[(2-Fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (intermediate 41, 150 mg, 0.39 mmol), was stirred in DMF (4 mL) and pyridine (1 mL). Benzoyl chloride (60 mg, 0.43 mmol) was added and the reaction stirred for 18 h. Water (20 mL) was added and the reaction mixture thoroughly mixed. The resulting precipitate was filtered, washed with water (2×10 mL) then ether (2×10 mL) and dried in vacuo to give the title compound (130 mg) as a pale purple solid:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccc(Br)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Br)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-bromophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.72 (1H, s), 7.30-7.32 (2H, m), 7.41 (1H, d, J=0.8 Hz, J=5.2 Hz), 7.52-7.54 (2H, m), 7.56 (1H, d, J=0.8 Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.0 Hz). [M+H] Calc'd for C16H11BrN4O, 355; Found, 355.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:50][C:51]1[CH:59]=[CH:58][C:54]([CH:55]([OH:57])[CH3:56])=[CH:53][CH:52]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:57][CH:55]([C:54]1[CH:58]=[CH:59][C:51]([CH3:50])=[CH:52][CH:53]=1)[CH3:56]
Reactant: Cc1ccc(C(C)O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccc(C)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 52.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (106 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methyl-α-methylbenzyl alcohol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 49%).
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O-:18])=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[K+].[N:20]1(C([O-])=O)C2C=CC=CC=2N=N1.[NH4+]>CN(C)C=O.O>[I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:20])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: Cn1nc(C(=O)[O-])c2c1-c1nc(I)ncc1CC2
Reactant: O=C([O-])n1nnc2ccccc21
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A suspension of potassium 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (394 mg, 1.0 mmol) in anhydrous dimethylformamide (10 mL) was treated with N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (287 mg, 1.5 mmol) and with ammonium 1H-1,2,3-benzotriazol-1-ate (304 mg, 2 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (320 mg, 90% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[I:17]N1C(=O)CCC1=O>C(#N)C>[I:17][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccn2cc(-c3ccncc3)nc2c1
Solvent: CC#N
Product: Cc1ccn2c(I)c(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 7-methyl-2-pyridin-4-ylimidazo[1,2-a]pyridine (6.52 g, 31.1 mmol), N-iodosuccinimide (7.0 g, 31.1 mmol) and ACN (180 ml) is stirred at RT for 17 h. The precipitate is collected, washed with ACN and dried. Yield: 4.4 g (42%). HPLC-MS: M+H=336; tR=1.55 min (*Method—3).
Reaction SMILES: Cl.[Br:2][C:3]1[N:12]=[C:6]2[CH2:7][CH:8]([NH2:11])[CH2:9][CH2:10][N:5]2[N:4]=1.C(Cl)Cl.[CH3:16][N:17]1[C:21]([C:22](Cl)=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[CH:19]=[N:18]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[Br:2][C:3]1[N:12]=[C:6]2[CH2:7][CH:8]([NH:11][C:22]([C:21]3[N:17]([CH3:16])[N:18]=[CH:19][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)=[O:23])[CH2:9][CH2:10][N:5]2[N:4]=1
Reactant: NC1CCn2nc(Br)nc2C1
Reactant: Cc1cccc(-c2cnn(C)c2C(=O)Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2cnn(C)c2C(=O)NC2CCn3nc(Br)nc3C2)n1
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
The 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (38 mg) obtained in (Example 5.16) <Step 6> was added at 0° C. to a methylene chloride (1 ml) solution of the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (35 mg) obtained in (Example 5.47) <Step 1> and triethylamine (0.06 ml). The obtained mixture was stirred for 30 minutes. Thereafter, a saturated sodium hydrogen carbonate aqueous solution (2 ml) was added to the reaction solution, and the mixed solution was then purified by LC/MS, so as to obtain the title compound (29 mg) in the form of a white solid.
Reaction SMILES: O.[CH2:2]([NH:9][C:10](=[O:19])[CH2:11][N:12]1[CH:15]([S:16][CH3:17])[CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:24]O)(C)(C)C>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:2]([NH:9][C:10](=[O:19])[CH2:11][N:12]1[CH:15]([S:16]([CH3:17])=[O:24])[CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OO
Reactant: CSC1CC(=O)N1CC(=O)NCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)C1CC(=O)N1CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4RSR-(-)-N-Benzyl-(4-methylsulphinyl-2-oxoazetidin-1-yl )acetamide A solution of S(-)1,1'-bi-2-napthol (0.012 g, 4.2 μmol) in toluene (2 ml) was treated with titanium isopropoxide (0.012 g, 21 μmol) in water (6 mg, 0.033 mmol). The resulting mixture was stirred at room temperature for 1 h. A solution of (-)-N-Benzyl (4-methylthio-2-oxoazetidin-1-yl)acetamide (0.2 g, 0.76 mmol) in toluene was added. After 30 mins t-butylhydroperoxide (136 mg, 1.5 mmol) was added and the mixture stirred for 3h. After evaporation to dryness, the residue was purified by flash chromatography on silica (EtOAc/EtOH 6:1 to 3:1) to give (-)-N-benzyl-(4-methylsulphinyl-2-oxoazetidin-1-yl)acetamide as a solid, 70 mg, 33% m.p. 138-140° C, [α]D25 =-237° (c=1.35, EtOH).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][O:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[O:7][C@@H:6]1[CH2:42][O:43]C(=O)C)(=O)C.[OH-].[Li+]>C1COCC1.CO.O>[Cl:34][C:22]1[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:42][OH:43])[O:7]2)=[C:20]([CH2:35][O:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[CH:21]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(COCC(O)CO)cc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC(O)CO)cc2Cl)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-2-((2,3-dihydroxypropoxy)methyl)-5-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (50 mg, 0.076 mmol) (prepared from intermediate J using a Sharpless dihydroxylation) in THF:MeOH:H2O (2:3:1, 1.2 mL) was added lithium hydroxide (3.71 mg). The reaction was stirred overnight at 20° C. The volatiles were removed and the residue was dissolved in EtOAc (20 mL), washed 1× with brine, 1× with brine containing 2 mL of 5% aqueous KHSO4 and dried over Na2SO4. Concentration gave 3.5 mg of pure product as a white solid. 1H-NMR (CD3OD, 300 MHz) δ 7.45 (s, 1H), 7.43 (s, 1H), 7.08 (s, 4H), 4.75-4.70 (m, 2H), 4.60-4.45 (m, 2H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.93-3.83 (m, 2H), 3.87-3.77 (m, 2H), 3.66-3.36 (m, 7H), 2.60 (q, J=7.8 Hz, 2H), 1.21 (t, J=7.8 Hz, 3H), 1.15 (d, J=7.8 Hz, 3H); LC-MS (m/z) 497 [(M+1)+], 541 [(M+45)−].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:21]([C:30]2[CH:35]=[CH:34][C:33](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:32]([N+:47]([O-:49])=[O:48])[CH:31]=2)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)([O-:3])=[O:2].[CH3:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.Cl>C(OCCCC)(=O)C>[N+:47]([C:32]1[CH:31]=[C:30]([C:21]([C:6]2[CH:7]=[CH:8][C:9]([N:51]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH3:50])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)([C:22]([F:23])([F:24])[F:25])[C:26]([F:28])([F:29])[F:27])[CH:35]=[CH:34][C:33]=1[N:51]([CH3:50])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([O-:49])=[O:48]
Reactant: CNCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C(c3ccc(OS(=O)(=O)c4ccc(C)cc4)c([N+](=O)[O-])c3)(C(F)(F)F)C(F)(F)F)cc2[N+](=O)[O-])cc1
Agent: Cl
Solvent: CCCCOC(C)=O
Product: CN(Cc1ccccc1)c1ccc(C(c2ccc(N(C)Cc3ccccc3)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
3 g (4.08 mmol) of 2,2-bis-(3-nitro-4-tosyloxyphenyl)hexafluoropropane was dissolved in 70 ml of butyl acetate, followed by moderately heating and refluxing. Then 5.26 ml (40.8 mmol) of n-methylbenzylamine was added dropwise into the solution, and after heating and refluxing were continued for 12 hours, the solution was cooled to room temperature. After 20 ml of dilute hydrochloric acid was added and extraction with ethyl acetate was carried out two times, an organic layer was washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and saturated brine. After the washed organic layer was dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained liquid product was separated by silica gel chromatography (hexane/ethyl acetate=4/1, hexane/dichloromethane=1/1) to obtain 2.1 g (yield: 81%) of 2,2-bis-[3-nitro-4(N-methyl-N-benzylamino)phenyl]hexafluoropropane in the form of yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:6]=2[CH:5]=[C:4]([F:19])[CH:3]=1.BrC1C=C(F)C=CC=1O.FC1C=C(C=CC=1)C=CC=O.[Cl:40][S:41](O)(=[O:43])=[O:42].N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.O>[Br:1][C:2]1[C:10]2[O:9][C:8]([S:41]([Cl:40])(=[O:43])=[O:42])=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:6]=2[CH:5]=[C:4]([F:19])[CH:3]=1
Reactant: Fc1cccc(Cc2coc3c(Br)cc(F)cc23)c1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=CC=Cc1cccc(F)c1
Agent: Oc1ccc(F)cc1Br
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Cl)c1oc2c(Br)cc(F)cc2c1Cc1cccc(F)c1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
7-Bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran (0.97 gm, 3.0 mmol, prepared from 2-bromo-4-fluoro-phenol and 3-fluoro-cinnamaldehyde following the procedure of steps 1 and 2 of Example 8) was dissolved in dichloromethane (30 ml) and chilled to −15° C. Chlorosulfonic acid (0.26 ml, 3.9 mmol) in dichloromethane (2 ml) was added in portions, and the reaction mixture was stirred for 10 minutes then warmed to room temperature and stirred for 16 hours. To the resulting slurry was added pyridine (0.33 ml, 4.08 mmol) and phosphorus pentachloride (0.812 gm, 3.9 mmol) and the reaction mixture was stirred for 24 hours. Water was added and the reaction mixture was stirred for 30 minutes. The organic layer was separated, dried over magnesium sulfate, dried onto silica gel, and layered over a pad of silica gel in a fritted funnel. The silica gel was eluted with ethyl acetate/hexanes (1/9) to give 7-bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-2-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:6])C([O-])=O.[Na+].[C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:11])[CH3:10].O>COCCOCCOC>[C:9]([O:12][CH2:13][C@H:14]1[C@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]1([Cl:6])[Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC/C=C/c1ccccc1
Reactant: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: CC(=O)OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of sodium trichloroacetate (27.8 g, 150 mmol) in diglyme (20 ml) was added dropwise over 1 hour to a solution of trans-cinnamyl acetate (8.81 g, 50 mmol) in diglyme (80 ml) at 120° C. to 135° C. and the reaction mixture was heated at 120° C. to 125° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into water (300 ml), extracted with n-hexane (300 ml+3×50 ml) and dried over MgSO4. The solvent was removed and the residue was distilled under vacuum affording the title compound (11.0 g, 76% yield, b.p. 104-105° C. (0.15 mmHg)).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][NH:30]C(=O)C6C(=CC=CC=6)C(O)=O)[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.C(O)C.NN>>[F:42][C:2]([F:1])([F:43])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][NH2:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1
Reactant: O=C(O)c1ccccc1C(=O)NCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: NN
Solvent: CCO
Product: NCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 60 °C
Yield: 9 %

Procedure:
To a solution of N-[2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-phthalamic acid (0.2000 g, 0.0003281 mol) in ethanol (3 mL, 0.05 mol) was added hydrazine (0.01133 mL, 0.0003609 mol). The mixture was heated to 60° C. overnight, cooled to room temperature and concentrated in vacuo. The crude was purified by reverse-phase HPLC to give 344 (13.6 mg) as a colorless solid. MS (ESI+) 462.1. 1H NMR (400 MHz, DMSO) δ 8.31-8.25 (m, 3H), 7.99 (s, 1H), 7.45 (dd, J=8.3, 1.8, 1H), 7.33 (d, J=1.8, 1H), 5.87 (q, J=8.7, 2H), 4.40 (t, J=5.0, 2H), 4.11 (t, J=6.3, 2H), 3.47 (t, J=5.0, 2H), 2.98 (t, J=6.3, 2H)
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]([CH3:40])[C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH2:19][N:20]([CH3:40])[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)[CH2:3][CH2:2]1
Reactant: CN(CCCBr)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(N2CCNCC2)c(C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCN1CCN(c2ccccc2C2CC2)CC1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 96 °C
Yield: 18.2 %

Procedure:
9.0 g (0. 0444 mol) of 1-(2-cyclopropylphenyl)piperazine, 200 ml of dimethylformamide, 17.5 g (0.0444 mol) of 3-bromo-N-methyl-N-(triphenylmethyl)propanamine and 9 g of potassium carbonate are introduced into a 500 ml round-bottomed flask equipped with a reflux condenser and placed under nitrogen, and the mixture is heated three times for 6 h at 96° C. The solvent is evaporated under reduced pressure, the residue is taken up with water and dichloromethane, the organic phase is separated, washed with water, dried over sodium sulphate and the solvent is evaporated under reduced pressure. There are obtained 4.17 g of 3-[4-(2-cyclopropylphenyl)piperazin-1-yl]-N-methyl-N-(tri-phenylmethyl)propanamine in the form of an oil which is dissolved in 200 ml of methanol, a stream of gaseous hydrochloric acid is passed therein for 10 min, the mixture is concentrated, allowed to stand for 2 days and the precipitate is separated by filtration. 2.94 g of compound are obtained.
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([NH:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH2:25][CH3:26])[N:24]=2)[CH2:17]1)=O)(C)(C)C.CO>O1CCOCC1>[NH2:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH2:25][CH3:26])[N:24]=2)[CH2:17]1
Reactant: CCc1nc(N2CC(NC(=O)OC(C)(C)C)C2)sc1C(=O)OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1nc(N2CC(N)C2)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 95 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (1.02 mL, 4.07 mmol) was added to a solution of methyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-4-ethyl-1,3-thiazole-5-carboxylate obtained in Example (222a) (139 mg, 0.41 mmol) in 1,4-dioxane (4 mL) at room temperature, and the mixture was stirred at room temperature for 13 hours. Then, methanol (2 mL) was added, and the mixture was further stirred for 5.5 hours. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution was added to the resulting residue. Thereafter, the mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure to obtain 94 mg of the title compound as a pale yellow oily substance (96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C1COCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH3:10])([CH3:11])[O:12][C:18](=[O:19])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(O)c1ccc(Br)cc1N
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Into the solution of 2-(2-amino-4-bromophenyl)propan-2-ol (2.3 g) in THF (50 mL) was added CDI (1.95 g) at rt., then the mixture was warmed to 60° C. and stirred for overnight. After solvent removal, the residue was dissolved in ethyl acetate and washed with 1M of HCl(aq) and brine, and dried with dry agent. After removal of the solvent, the residue was crystallized from DCM and hexane to provide 2.3 g of 7-bromo-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.37 was synthesized. LCMS [M+H]+: 252.71. 1H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 7.18 (d, d, J=8.2, 1.8 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 1.71 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(#N)C>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:10][CH:9]=3)[C:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:6]2[C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccc(-c2ccccc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc2c(c1)c(-c1ccccc1)c(C(=O)O)n2Cc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-(1,1′-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate and methanesulfonyl chloride followed the procedure of Example 1 Step 3 as a white solid: 1H NMR (DMSO-d6) δ 2.86 (s, 3H, 5.87 (s, 2H), 7.22 (d, J=8.4 Hz, 2H, 7.25 (dd, J=9.0, 2.1 Hz, 1H, 7.30-7.40 (m, 3H, 7.40-7.50 (m, 6H), 7.58-7.63 (m, 4H, 7.66 (d, J=9.0 Hz, 1H, 9.40 (s, 1H, 12.52 (br s, 1H; MS (ESI) m/z 495 [M-H]−; HRMS calcd for C29H25N2O4S: 497.1533; found (ESI+): 497.1524; Anal. calcd for C29H24N2O4S.0.5H2O.0.5 ACN: C, 68.49; H, 5.05; N, 6.66. Found: C, 68.05; H, 5.04; N, 7.04.