Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:29]C(=O)OC(C)(C)C)[C@@H:9]([OH:28])[CH:10]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])OC(CC)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH2:29][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([OH:28])[CH2:10][N:16]([O:26][CH:23]([CH2:22][CH3:21])[CH3:24])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: CCC(C)OC(NS(=O)(=O)c1ccc(OC)cc1)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)ON(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-sec-butoxy[(4-methoxyphenyl)sulfonyl]amino-2-hydroxy-propyl)carbamate (1.9 mmol, 1 g) was stirred in neat trifluoroacetic acid (TFA) at room temperature for 1 hour. The TFA was removed under vacuum, and the resulting residue was dissolved in ethyl acetate, washed with 5% aq. potassium carbonate solution, brine and dried over magnesium sulfate. The dried solution was concentrated under vacuum and stored as a sticky white solid. H1-NMR (CDCl3): δ 7.81 (2H,d), 7.28-7.16 (5H,m), 7.01 (2H,d), 4.31 (2H,bs), 4.01-3.90 (1H,bs), 3.88 (3H,s), 3.5-2.5 (1H,bs), 3.33(2H,bs), 2.89 (2H,bs), 2.63(2H,bs), 1.71 (1H,bs), 1.43-1.40 (1H,m), 1.27-1.19 (3H,m), 0.98-0.85 (3H,m); MS (ESI): M+H=423.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][N:3]=1.BrC1N2CCN(C(OC(C)(C)C)=O)CC2=NN=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:58][C:59]1[C:67]([C:68]([F:71])([F:70])[F:69])=[CH:66][CH:65]=[CH:64][C:60]=1[C:61](Cl)=[O:62]>ClCCl>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:61]([C:60]3[CH:64]=[CH:65][CH:66]=[C:67]([C:68]([F:69])([F:70])[F:71])[C:59]=3[Cl:58])=[O:62])[CH2:10][C:5]2=[N:4][N:3]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: Brc1nnc2n1CCNC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Reaction time: 4 h

Procedure:
3-Bromo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (prepared by standard BOC deprotection of tert-Butyl 3-bromo-5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate, CAS [723286-80-4], commercially available e.g. from Allichem, Ark Pharm or Bepharm) (0.6 mmol) and diethylaminomethyl polystyrene (0.6 g, 1.92 mmol) were slurried in Dichloromethane (DCM) (7 mL) under argon. 2-Chloro-3-(trifluoromethyl)benzoyl chloride (0.16 g, 0.66 mmol, commercially available e.g. from Apollo Scientific or Shanghai FWD Chemicals) was added to the reaction. The mixture was stirred for 4 hours. The resin was filtered, washed with Dichloromethane (50 mL) and concentrated in vacuo to afford crude product. The crude product was purified by using mass-directed automated (preparative) HPLC (MDAP). The fractions containing the products were evaporated, diluted with diethyl ether and treated with 1 mL of HCl in diethyl ether; the solutions were stirred for 30 min. and solvent evaporated to give 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.268 g). LC/MS [M+H]+=410.9, retention time=2.07 minutes (5 minute method).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>CO>[CH3:15][O:16][CH:17]([O:21][CH3:22])[N:11]1[CH2:12][CH2:13][CH2:14][CH:8]([CH2:7][CH2:6][C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)[CH2:9][CH2:10]1
Reactant: C1CNCCC(CCC2=NCCN2)C1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(OC)N1CCCC(CCC2=NCCN2)CC1
Temperature: 90 °C

Procedure:
A mixture containing rac-4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine (1.95 g, 0.01M), methanol (50 ml) and dimethylformamide dimethylacetal (36 ml) was heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed in vacuo to give 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine-1-carboxaldehyde dimethylacetal to the mixture of 6-aminopenicillanic acid (1.95 g, 0.009M) and diisopropylethylamine (1.52 ml) in dry chloroform (25 ml) was added the solution fo the above hexahydroazepine carboxaldehyde dimethylacetal in dry chloroform (10 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr. and at room temperature for 3 hrs. After the reaction solvent was removed and the residue dissolved in water (30 ml). The aqueous solution, washed with ethylacetate was acidified to pH 3 with dil. HCl and purified on Sephadex LH 20 columns to give [ 2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (1.03 g, 27% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:14])([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)Cl.CCOCC>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]([CH3:14])([OH:13])[CH2:11][O:12][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CO)COCc1ccccc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(O)(COCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 -Benzyloxymethyl-1-methyl-ethane-1, 2-diol (5g) in dimethylformamide (25 ml) was treated with sodium hydride (0.65g), the reaction mixture was stirred at ambient temperature for 1 h. then at 90° C for 15 min. The reaction mixture was cooled and benzyl chloride (3.3g) added; it was stirred for 4 h. at ambient temperature. The solvent was evaporated and the product isolated by chromatography on silica gel using methylene chloride/ether (9/1) to give the desired product as a colourless oil. The 1,3-configuration was confirmed by n.m.r. which showed the methylene groups of the carbon backbone to be equivalent, hence, establishing the symmetry of the molecule.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[C:13](O)=[O:14].C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O.[OH-].[Na+]>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14]
Reactant: Cc1onc(-c2ccncn2)c1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccncn2)c1CO
Temperature: -10 °C
Yield: 18.8 %

Procedure:
To a solution of 5-methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid (300 mg, 1.46 mmol) in THF (4 mL) at −10° C. was added triethylamine (203 μL, 1.46 mmol) and then a solution of ethylchloroformate (139 μL, 1.46 mmol) in THF (1 mL) added keeping the temperature below −5° C. After 1 h the mixture was filtered and the filtrate cooled to −10° C. and a suspension of sodiumborohydride (138 mg, 3.66 mmol) in water (1.5 mL) added over 15 minutes keeping the temperature below −5° C. The mixture was then allowed to warm up to room temperature over 2 h and diluted with aqueous sodium hydroxide (1 N) and extracted with ethylacetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=9:1) afforded the title product (52.5 mg, 19%) which was obtained as white solid. MS: m/e=190.0 [M−H]−.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)/[C:32]([OH:34])=O.[F:50][C:51]1[CH:60]=[CH:59][C:54]([C:55]([NH:57][NH2:58])=O)=[CH:53][CH:52]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[Cl:27][CH2:28][CH2:29][CH2:30]/[C:31](/[C:32]1[O:34][C:55]([C:54]2[CH:59]=[CH:60][C:51]([F:50])=[CH:52][CH:53]=2)=[N:57][N:58]=1)=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(/C=C(\CCCCl)c2nnc(-c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
IPEA (1.2 mL), EDC (0.89 g) and HOBT (0.62 g) were added to a suspension of 5-chloro-2-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}valeric acid trifluoroacetic acid salt (1.30 g) and 4-fluorobenzhydrazide (0.37 g) in DMF (25 mL) at room temperature, and the reaction solution was stirred at room temperature for two hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. A solution of the resulting residue in phosphorus oxychloride (6 mL) was heated under reflux for three hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 376 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19]([OH:21])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:2]1.Cl.[F:23][C:24]1([F:32])[CH2:28][NH:27][C@@H:26]([C:29]([NH2:31])=[O:30])[CH2:25]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19]([N:27]3[CH2:28][C:24]([F:32])([F:23])[CH2:25][C@@H:26]3[C:29]([NH2:31])=[O:30])=[O:21])=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:17])([F:18])[C:13]([F:14])([F:16])[F:15])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1
Reactant: NC(=O)[C@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@H]1CC(F)(F)CN1C(=O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (30 mg, 96 μmol) and (2R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 1315053-41-8; 19.8 mg, 106 μmol) as starting materials and isolated (38 mg, 89%) as white solid; LC-MS (UV peak area, ESI) 97%, 444.1155 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(Cl)c(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc(Cl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 94.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4,5-dichloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (115 mg, 0.258 mmol) was dissolved in acetonitrile (8.1 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (134 mg, 1.03 mmol), acetic acid (0.295 mL, 5.16 mmol) and sodium triacetoxyborohydride (191 mg, 0.903 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4,5-dichloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (136 mg, yield 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: COc1c(C)cc(N)cc1C
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)cc(NC(C)=O)cc1C
Temperature: 50 °C
Yield: 82.6 %

Procedure:
4-Amino-2,6-dimethylanisole (4, 5 g, 33.2 mmol) was placed in a round-bottom flask fitted with a reflux condenser, and acetic anhydride (3.4 mL, 35.4 mmol) and acetic acid (3 mL, 53.1 mmol) were added sequentially. The mixture was heated to 50° C. for 4 h, cooled, poured into water and basified with saturated aq. sodium bicarbonate. The solution was extracted with methylene chloride, and the combined extracts were washed with brine and dried (MgSO4). Removing the solvent and recrystallizing the resulting solid from hexane-methylene chloride yielded 4-acetamido-2,6-dimethylanisole (7, 5.3 g, 83% yield). Spectral data: 1H NMR: δ 2.1 (s, 3H), 2.2 (s, 6H), 3.65 (s, 3H), 7.10 (s, 2H), 8.10 (s, 1H); 13C NMR: δ 16.1, 24.2, 60.0, 121.5, 131.8, 134.3, 154.3, 169.8; CI-HRMS: calcd. for C11H16NO2 (M+H+) 194.1181, fnd. 194.1181.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:13])[C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:13][CH:21]([CH3:23])[CH3:22])[C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2]
Reactant: CCOc1cc(O)c(F)c(C=O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)c(F)c(OC(C)C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a solution of Intermediate 7.1 (assumed 24.3 mmol) in 50 mL DMF, was added K2CO3 (4.03 g, 29.2 mmol) and 2-iodopropane (4.86 mL, 48.6 mmol). The mixture was stirred at 50° C. for 16 h, then was diluted with EtOAc/hexanes (1:1). The organic phase was washed with H2O (3×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 3.94 g of Intermediate 7.2 as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@H:27]4[CH2:28][CH2:29][O:25][CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: N[C@H]1CCOC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N[C@H]3CCOC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-tetrahydrofuran-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84-2.02 (m, 1H) 2.09-2.27 (m, 1H) 2.43 (s, 3H) 3.63 (dd, J=8.84, 4.04 Hz, 1H) 3.73 (td, J=8.08, 5.81 Hz, 1H) 3.83-3.95 (m, 2H) 4.42-4.58 (m, 1H) 7.66 (d, J=7.83 Hz, 1H) 7.73 (s, 1H) 7.77 (br. s., 1H) 8.18 (br. s., 1H) 8.44 (d, J=6.82 Hz, 2H) 8.78 (d, J=6.32 Hz, 1H) 8.92 (s, 1H) 13.18 (br. s., 1H). MS m/z [M+H]+ 390.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([C:2]2[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=2)[CH:23]=1)#[N:17]
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Reactant: COc1ccc(C#N)cc1B(O)O
Product: COc1ccc(C#N)cc1-c1cc(S(N)(=O)=O)cc(C=O)c1OC

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 5-cyano-2-methoxy-benzeneboronic acid, gave 5′-cyano-5-formyl-6,2′-dimethoxybiphenyl-3-sulfonamide.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br>ClCCCl>[Br:21][C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[C:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: C(=C(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: BrC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Into a reactor were introduced 12.5 g (48.8 mmol) of the 1,1,2-triphenylethylene and 50 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to 0° C., and 7.80 g (48.8 mmol) of bromine was gradually added dropwise thereto. This mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium thiosulfate solution, and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The resultant concentrate was recrystallized from ethanol and ethyl acetate to obtain 11.3 g (69%) of the target compound as white crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccn1
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Product: O=C(Nc1ccccn1)Nc1ccccc1Oc1ccccc1
Yield: 71.4 %

Procedure:
N-(2-Phenoxyphenyl)-N′-(pyridin-2-yl)urea (109 mg, 72%) was prepared from 2-phenoxyphenylisocyanate (106 mg, 0.5 mmol) and 2-aminopyridine (60 mg, 0.6 mmol) following the general procedure E.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=1[NH2:16])(=O)C.[N:17]([O-])=O.[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[NH:4]1[C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[N:16]=[N:17]1
Reactant: COC(=O)Cc1ccc(NC(C)=O)c(N)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
Methyl 4-acetamido-3-aminophenylacetate (77 g, 0.373 mol) was taken up in a mixture of acetic acid (210 ml) and water (210 ml) and cooled to below 5° C. A solution of sodium nitrite (38.63 g, 0.559 mol) in water (200 ml) was added dropwise, and once the addition was complete the mixture was stirred for 4 hours, warming slowly to room temperature. The mixture was diluted with ethyl acetate and the insoluble material removed by filtration. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated in vacuo, to give a viscous residue (51 g) which was then dissolved in a solution of methanol (400 ml) previously saturated with hydrogen chloride and the mixture stirred for 2 hours. The solvent was removed in vacuo, the residue taken up in water, neutralised with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to afford methyl 5-benzotriazoleacetate (35 g) as a reddish liquid which crystallised on standing.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12]C=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][C:17]([OH:19])=[O:18].OS(O)(=O)=O>O>[C:6]([C:8]1[CH:13]=[CH:12][C:16]([C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1)(=[O:7])[C:5]1[CH:14]=[CH:15][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 100 °C

Procedure:
To a mixture of 4-methylbenzophenone (25 g, 0.127 mole) with HOAc (130 mL) was added successively CrO3 (35 g), H2O (80 mL) and conc. H2SO4 (25 mL). The mixture was heated for 3 hours at 100±5° C. and then quenched by adding ice water (500 mL) to yield a crude 4-benzoylbenzoic acid solid which was dissolved in a 10% KOH solution and filtered. The filtrate was acidified with diluted HCl to pH 2.0 and precipitate by subjected to ice bath. The precipitate was collected to obtain 21.3 g 4-benzoylbenzoic acid in a yield of 74.1%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[CH:58][C:57]=1[S:61](Cl)(=[O:63])=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:57]2[CH:58]=[N:59][O:60][C:56]=2[CH3:55])(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1oncc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oncc1S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 12 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-4-sulfonyl chloride as starting materials in 12% yield. LCMS for C28H30ClN8O4S (M+H)+: m/z=609.2.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=1>>[F:43][C:40]1[CH:39]=[N:38][C:37]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[N:42][CH:41]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Fc1cnc(Cl)nc1
Product: C[C@@H](c1ccc(-c2ncc(F)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one and 2-chloro-5-fluoropyrimidine a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.327 min, m/z=391.9; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.52 (d, 3H), 2.20 (m, 4H), 2.38 (m, 1H), 2.85 (m, 1H), 5.72 (m, 1H), 7.08 (m, 2H), 7.20-7.40 (m, 5H), 8.12 (m, 2H), 8.61 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH2:9]=O>FC(F)(F)C(O)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[CH2:9])=[N:3][CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: C=O
Solvent: O=C(O)C(F)(F)F
Product: C=Nc1ccc(I)cn1
Yield: 76.6 %

Procedure:
Add trifluoroacetic acid (3 drops) to a suspension of 2-amino-5-iodopyridine (1.0 g, 4.5 mmol) and paraformaldehyde (1.0 g). Heat the mixture at reflux for 15 h and concentrate. Purification by flash chromatography eluting with ethyl acetate gives 0.8 g (75%) of the title compound as a white solid. ES+ m/e 232.6 (M+1).