Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C1COCC1.[Br-].[CH:19]1([CH2:25][Zn+])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1CCCC1=O>[CH:19]1([CH2:25][C:2]2[S:3][C:4]3[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1ccc2nc(Br)sc2c1
Reactant: [Zn+]CC1CCCCC1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2nc(CC3CCCCC3)sc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Place 2-bromo-benzothiazole-6-carbonitrile (0.2 g, 0.96 mmol), anhydrous THF (3 mL), 1-methyl-2-pyrrolidinone (3 mL), tetrabutylammonium iodide (1.1 g, 2.89 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.09 mmol) and [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II) (11 mg, 0.09 mmol) in a flask. Add 0.5M cyclohexylmethylzinc bromide in THF (3.8 mL, 1.92 mmol) to the mixture, degas 3 times by partially evacuating the atmosphere and flushing with nitrogen and stir the reaction mixture at 80° C. for 2 h. Cool the reaction mixture to room temperature, dilute with EtOAc (10 mL) and wash with brine (10 mL). Dry the organic layer over anhydrous Na2SO4, filter and concentrate in vacuo. Purity the residue by chromatography on silica gel eluting sequentially with hexane/EtOAc (1:0 to 4:1 gradient) to obtain the desired intermediate as a yellow solid (140 mg, 57%). GC-MS m/z: 256 (M+).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].[BH4-].[Na+].[Cl:27][C:28]([F:33])([F:32])[C:29](O)=O>>[Cl:27][C:28]([F:33])([F:32])[CH2:29][N:4]1[C:5]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[O:23][CH2:24][C@H:3]1[CH2:1][CH3:2]
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Reactant: O=C(O)C(F)(F)Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC(F)(F)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
This compound was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (22 mg, 0.06 mmol) and NaBH4 pellets (large excess, >10 equiv) in 4 mL chlorodifluoroacetic acid (0.02 M) stirred at rt for 12 h, to afford 17 mg (61%) of (3R)-4-(2-chloro-2,2-difluoroethyl)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. 1H NMR (500 MHz, CDCl3) 7.44 (d, 1H, J=9.3), 7.32 (d, J=1H, 9.3), 7.21 (s, 1H), 5.50 (m, 1H), 4.39 (dd, 1H, J=10.7, 1.5), 4.09 (m, 1H), 3.99 (dd, 1H, J=10.7, 2.4), 3.92 (m, 1H), 3.33 (m, 1H), 1.6 (m, 2H), 1.39 (d, 3H, J=6.3), 1.38 (d, 3H, J=6.3), 0.99 (t, 3H, J=7.3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccccc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 23 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 2-Chlorobenzaldehyde (39.4 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 24.35 mg (23%) of the title compound. (300 MHz, DMSO-d6) 13.15 (s, 1H), 7.99 (s, 1H), 7.84 (m, 1H), 7.74 (s, 1H), 7.64 (m, 1H), 7.53 (m, 2H), 7.20 (m, 2H), 6.29 (s, 2H), 5.14 (t, J=17 Hz, 8.5 Hz, 1H), 2.86 (s, 1H), 2.79 (s, 1H), 2.58 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=414 (M+H), HPLC: 2.49 min. (G Method)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])=[C:7]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (2.19 g, 4.65 mmol) in anhydrous dichloromethane (50 mL) at 0° C. was added Dess-Martin Periodinane (2.76 g, 6.51 mmol) portion-wise over 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour and quenched with sodium thiosulfate solution and saturated sodium bicarbonate solution and stirred for 30 minutes. The mixture was diluted with ethyl ether and washed with saturated sodium bicarbonate solution (3×), brine and dried (MgSO4), filtered, concentrated to give a yellow oil with a white precipitate. The mixture was suspended in diethyl ether, washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C-:20]#[N:21].[Na+]>C(#N)CC.[Cu](I)I>[C:20]([C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:21]
Reactant: COC(=O)c1cc(Br)cnc1Oc1ccc(F)cc1
Reactant: [C-]#N
Agent: I[Cu]I
Agent: [Na+]
Solvent: CCC#N
Product: COC(=O)c1cc(C#N)cnc1Oc1ccc(F)cc1
Yield: 71.3 %

Procedure:
A mixture of methyl 5-bromo-2-(4-fluorophenoxy)nicotinate (step 1, 163 mg, 0.50 mmol), sodium cyanide (49 mg, 1.0 mmol), tetrakis(triphenylphohphine) palladium(0) (29 mg, 0.025 mmol), and copper iodide (9.5 mg, 0.05 mmol) in propionitrile (4.0 mL) was heated under reflux for 4.5 h with stirring. The reaction mixture was filtered through a pad of Celite®. The filtrate was partitioned between water (10 mL) and dichloromethane (30 mL). The organic phase was separated, dried (sodium sulfate), and concentrated. The residue was purified by TLC plate developing with hexane/ethyl acetate (3/1) to afford 97 mg (71%) of the title compound: 1H-NMR (CDCl3) δ 8.5 (2H, m), 7.14 (2H, d, J=1.2 Hz), 7.12 (2H, s), 3.99 (3H, s); MS (ESI) m/z 272 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)#[CH:35].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:35]#[C:34][C:36]3[CH:37]=[CH:38][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][CH:41]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.46 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 168 mg (57%). HPLC-MS: m/z: 642.1 (M+H)+; Rt: 2.75 min
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH:4]=[C:5]3[C:11]4[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=4[O:9][CH2:8][C:7]4[N:18]=[CH:19][CH:20]=[CH:21][C:6]3=4)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution the product of step 2 (1.1 g) in DMF (15 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (0.81 g) and potassium carbonate (0.53 g) and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound as major regioisomer (0.86 g) and minor one (0.05 g).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1([O:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=4[O:39][CH3:40])[C:24]=3[CH:41]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:11]1([O:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:38]=[CH:37][C:33]([C:34]([NH:10][S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])=[O:35])=[CH:32][C:31]=4[O:39][CH3:40])[C:24]=3[CH:41]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1cc(C(=O)O)ccc1CN1CCOc2ccc(NC(=O)OC3CCCC3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1CN1CCOc2ccc(NC(=O)OC3CCCC3)cc21
Reaction time: 21 h
Yield: 53.5 %

Procedure:
Benzenesulphonamide (0.037 g.) was added to a stirred solution of 4-[6-(cyclopentyloxycarbonyl)amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl]-3-methoxybenzoic acid (0.1 g.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.046 g.) and 4-(dimethylamino)pyridine (0.029 g.) in dichloromethane (5 ml.), under an atmosphere of nitrogen. The mixture was stirred for 21 hours and then diluted with dichloromethane. This mixture was washed successively with 1M hydrochloric acid (2×10 ml.), 5% w/v sodium bicarbonate solution (2×10 ml.), and saturated brine (20 ml.). It was then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (3 cm. diameter column) eluting with 1:1 v/v ethyl acetate:hexane. The solid obtained was recrystallized from ethyl acetate to give the title compound as a white powder (0.071 g., 54%), m.p. 186°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([N:30]=[CH:31][C:32]=3[C:33]([OH:35])=O)[C:21]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH2:10][CH2:9]1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([N:30]=[CH:31][C:32]=3[C:33]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:35])[C:21]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH2:12][CH2:13]1
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCN(c3ccccc3Cl)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCN(c4ccccc4Cl)CC3)cnc12
Yield: 19.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(2-chlorophenyl)piperazine-1-carbonyl]-7-(2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.110 g, 0.224 mmol) obtained in step 2 and ethanesulfonamide (0.049 g, 0.448 mmol), the title compound (0.025 g, 19%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:19]#[N:20])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:27]#[N:28].[NH2:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33].O>C1COCC1>[C:19]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([NH:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:3]([C:27]#[N:28])[C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1c(Cl)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccccc1
Reactant: NC[C@@H](O)CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(NC[C@@H](O)CO)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
61.5 mg (0.15 mmol) of 3-{[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}benzenecarboxylic acid (Example 72A) were initially charged in 1.6 ml of THF. After addition of 27.6 mg (0.30 mmol) of (2R)-3-aminopropane-1,2-diol, the mixture was stirred at RT overnight. 2 ml of water were added, and the reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27](=O)[CH2:28]Br>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:28]=[C:27]([C:26]3[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=3[C:24]([F:23])([F:35])[F:36])[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccccc3C(F)(F)F)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 19 %

Procedure:
2′-Nitro-4-[4-(2-trifluoromethyl-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (56 mg, 19%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-(trifluoromethyl)phenacyl bromide (available from Maybridge) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.06 (br s, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.20 (dd, J=8.2, 1.7 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.64-7.80 (m, 4H), 7.40-7.46 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)(=[O:29])=[O:28]>>[CH2:24]([NH:23][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:27]([CH3:26])(=[O:29])=[O:28])[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)=[CH:15][CH:16]=1)=[O:22])[CH3:25]
Reactant: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOCC3)n2)cc1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Product: CCNC(=O)Nc1ccc(-c2cc(-c3ccccc3S(C)(=O)=O)nc(N3CCOCC3)n2)cc1
Yield: 10 %

Procedure:
Method as described for Example 8 using 1-(4-(6-chloro-2-morpholinopyrimidin-4-yl)phenyl)-3-ethylurea and (2-methylsulfonylphenyl)boronic acid. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMSO, filtered and purified by prep HPLC (low pH) to afford a white solid (13.2 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16].[H-].[Na+]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:23][C:22]1[C:17]([C:15]([O:14][CH3:13])=[O:16])=[N:18][CH:19]=[CH:20][N:21]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1nccnc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nccnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.5 %

Procedure:
To a stirred solution of 2,3-dichlorobenzenesulphonyl chloride (0.246 g) and methyl-3-aminopyrazine-2-carboxylate (0.153 g) in 1,2-dimethoxymethane (3 mL) was added portionwise sodium hydride (0.1 g of a 60% dispersion in oil) over 1 hour. The mixture was stirred at room temperature for 20 h, was poured into water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with dichloromethane to afford the titled compound (0.085 g) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Mg]Br.[CH3:8][N:9]([CH3:32])[C:10]1(C#N)[CH2:15][CH2:14][CH:13]([CH:16]([O:24][CH:25]([O:27][CH2:28][CH3:29])[CH3:26])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:28]([O:27][CH:25]([O:24][CH:16]([CH:13]1[CH2:14][CH2:15][C:10]([N:9]([CH3:32])[CH3:8])([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:12]1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:26])[CH3:29]
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)OC(Cc1ccccc1)C1CCC(c2cccs2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1 M solution of 2-thienylmagnesium bromide in tetrahydrofuran (9.25 ml, 9.25 mmol) was added dropwise to a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with ice and under an argon atmosphere. The mixture was stirred at room temperature for 48 h and water and saturated ammonium chloride solution (10 ml of each) were then added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22])[C:13]=2[CH:12]=[C:11]([N+:27]([O-])=O)[CH:10]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl>CO.[Pd]>[CH2:1]([O:3][P:4]([C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([P:19]([O:20][CH2:21][CH3:22])(=[O:23])[O:24][CH2:25][CH3:26])[C:13]=2[CH:12]=[C:11]([NH2:27])[CH:10]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc([N+](=O)[O-])cc2c(P(=O)(OCC)OCC)cccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOP(=O)(OCC)c1cc(N)cc2c(P(=O)(OCC)OCC)cccc12

Procedure:
Tetraethyl3-nitronaphthalene-1,5-diphosphonate (4.00 g, 9.0 mmol) dissolved in methanol (150 ml) and 1N HCl aqueous solution (10 ml) was stirred with H2 and 5% Pd/C in PARR apparatus until H2 absorption ceased. After catalyst filtration on filter aid, the methanol was evaporated under reduced pressure; the residue was stirred with ethanol (10 ml) and diethyl ether (50 ml) and the separated crystalline solid was filtered, washed and dried to yield the title product isolated as the hydrochloride hemihydrate (3.78 g, decomp. 230°-240° C., 91%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].CC(C)([O-])C.[K+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[C:18]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)C2)cc1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
A solution of 1-benzyl-3-(4-nitro-phenoxy)-pyrrolidine (7.2 g, 24 mmol) and 1-chloromethanesulfonyl-naphthalene (5.8 g, 24 mmol) in THF was chilled in an ice bath, treated dropwise with 1.0 M potassium tert-butoxide in THF (55 mL, 55 mmol), stirred at ambient temperatures for 1 hour, 10 minutes, under nitrogen, poured into water, treated with solid sodium bicarbonate and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 40-60% ethyl acetate in hexane to give 1-benzyl-3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-pyrrolidine as a brown gum/foam, 5.7 g (47.1% yield), Mass spectrum (+EI, [M+H]+) m/z 503. 1HNMR (500 MHz, DMSO-d6): δ8.44-8.46 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.07-8.09 (m, 1H), 7.92-7.96 (m, 2H), 7.58-7.66 (m, 3H), 7.19-7.31 (m, 5H), 6.99 (dd, 1H, J=9.15 Hz and 2.81 Hz), 6.66 (d, 1H, J=2.81 Hz), 5.24 (d, 2H, J=2.20 Hz), 4.65-4.69 (m, 1H), 3.53 (s, 2H), 2.59-2.66 (m, 2H), 2.41-2.42 (m, 1H), 2.27-2.34 (m, 1H), 2.00-2.10 (m, 1H), 1.43-1.54 ppm (m, 1H).
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].S(Cl)([Cl:18])=O>>[Cl:18][CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CO
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Hydroxymethyl-2-methyl-7-nitrobenzo[b]furan (1.0 g) was added to thionyl chloride (1.8 ml) with ice cooling. The mixture was stirred at ambient temperature for 30 minutes and concentrated in vacuo. To the residue was added toluene and the mixture was concentrated again. The residue was crystallized from a mixture of diethyl ether and n-hexane to give 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (1.01 g).
Reaction SMILES: O[CH:2]([C:13]1[N:14]([CH3:24])[N:15]=[N:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:3][C:4]1[S:5][C:6]([C:10]([OH:12])=[O:11])=[C:7]([CH3:9])[N:8]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:9][C:7]1[N:8]=[C:4](/[CH:3]=[CH:2]/[C:13]2[N:14]([CH3:24])[N:15]=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[S:5][C:6]=1[C:10]([OH:12])=[O:11]
Reactant: Cc1nc(CC(O)c2c(-c3ccccn3)nnn2C)sc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)O
Temperature: 160 °C
Yield: 79.1 %

Procedure:
A suspension of 2-[2-hydroxy-2-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (152 mg, 0.44 mmol) in sulfuric acid (conc., 2.59 mL, 48.4 mmol) was heated at 160° C. under Ar for 7 h. After cooling to room temperature the mixture was poured into ice, adjusted to pH 4 with NaOH (6 N) and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (114 mg, 79%) as an a yellow solid after trituration from methanol-water. MS: m/e=326.2 [M−H]−.