Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][S:5]([N:8]([C@@H:10]([CH2:14][CH:15]=[CH2:16])[C:11]([OH:13])=O)[CH3:9])(=[O:7])=[O:6].[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[C@@H:25]([NH:34][CH2:35][C@@H:36]([OH:48])[C@@H:37]([NH2:47])[CH2:38][C:39]2[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41]([Cl:46])[CH:40]=2)[CH2:24]1)[CH:20]=[CH2:21]>>[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[C@@H:25]([NH:34][CH2:35][C@@H:36]([OH:48])[C@@H:37]([NH:47][C:11](=[O:13])[C@@H:10]([N:8]([CH3:9])[S:5]([CH2:4][CH2:3][C:2]([F:1])([F:18])[F:17])(=[O:6])=[O:7])[CH2:14][CH:15]=[CH2:16])[CH2:38][C:39]2[CH:40]=[C:41]([Cl:46])[CH:42]=[C:43]([Cl:45])[CH:44]=2)[CH2:24]1)[CH:20]=[CH2:21]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(Cl)cc(Cl)c2)c2cc(OC)ccc21
Reactant: C=CC[C@@H](C(=O)O)N(C)S(=O)(=O)CCC(F)(F)F
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(Cl)cc(Cl)c2)NC(=O)[C@H](CC=C)N(C)S(=O)(=O)CCC(F)(F)F)c2cc(OC)ccc21
Yield: 24 %

Procedure:
Step DM (1): (S)-2-(3,3,3-Trifluoro-N-methyl-propylsulfonamido)pent-4-enoic acid (33 mg, 0.11 mmol, from Preparation J) was coupled with (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol (50 mg, from Preparation BG) by a procedure analogous to Step DL (1) to afford 19.1 mg of (S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-yl)-2-(3,3,3-trifluoro-N-methylpropylsulfonamido)pent-4-enamide as a clear oil. LC-MS Rt 2.10 min (method A), (M+H)+=722.1, 724.0; HRMS (M+H)+=722.2031; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J=8.2, 1H) 7.18 (s, 1H) 7.08 (s, 2H) 6.95 (d of d, J=8.5, 2.1, 1H) 6.78 (d, J=8.8, 1H) 5.91 (m, 1H) 5.66 (m, 1H) 5.31 (d, J=17.4, 1H) 5.24-5/12 (m, 3H) 4.82 (d, J=4.6, 1H) 4.72 (br d, J=6.7, 1H) 4.21 (d of d, J=5.2, 5.2, 1H) 4.10 (m, 3H) 4.01 (m, 3H) 3.80 (s, 3H) 3.26 (d, J=12.2, 1H) 3.10 (m, 5H) 2.90-2.80 (m, 2H) 2.72-2.50 (m, 5H0, 2.56 (s, 3H) 2.44-2.31 (m, 2H) 1.32 (t, J=7.3, 2H) 1.24 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17].[SH2:19].[Na]>C(O)C>[CH3:7][N:6]1[C:2]([SH:19])=[C:3]([C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:4]([CH3:8])=[N:5]1
Reactant: S
Reactant: Cc1nn(C)c(Cl)c1C(=O)c1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nn(C)c(S)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 33.3 %

Procedure:
A mixture of 0.3 g. of 5-chloro-4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazole, 2.1 g. of sodium hydrogen sulfide 2 hydrate and 6 ml. of ethanol is heated under reflux on a water bath for 3 hours. After completion of the reaction, the ethanol is distilled off under reduced pressure from the reaction mixture and 15 ml. of water is added followed by extraction with benzene. To an aqueous layer is added conc. hydrochloric acid to adjust the pH to 1 and the mixture is extracted with chloroform. The extract is washed with water and then dried over anhydrous sodium sulfate. The solvent is distilled off from the extract to give the crude crystalline substance, which is then crystallized from n-hexane to give 0.10 g. of the desired product as yellow powders having a melting point of 85°-86° C. Yield 33.3%.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[OH-].[K+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1>CC(C)=O>[N:1]1([CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH2:20][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: BrCc1cccc(CBr)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: c1cc(Cn2cnc3ccccc32)cc(Cn2cnc3ccccc32)c1
Yield: 18.8 %

Procedure:
To a 1 L round bottom flask equipped with a stirbar was added 26.8 g benzimidazole (227 mmol) and 12.7 g (227 mmol) finely pulverized potassium hydroxide. These were stirred in 500 mL acetone for 20 minutes at reflux. 20.0 g (78.5 mmol) α,α′-dibromo-m-xylene was then added, and the solution was stirred at reflux for 6 hours followed by room temperature stirring for 72 hours. The cloudy solution was filtered, and the white solids rinsed with acetone. The resulting filtrate was dried on silica and partitioned on a silica gel column using a gradient of 100% acetonitrile→90% acetronitrile/10% MeOH as eluent. The product fractions were evaporated of solvent to give 5 g 1-[3-(1H-benzimidazole-1yl-methyl)benzyl]-1H-benzimidazole as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[CH:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][SH:21]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH:8]2[C:9]3([CH2:14][C:15](=[O:17])[NH:18][CH2:19][CH2:20][S:21]3)[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=C1CCCCC1Cc1ccccc1
Reactant: NCCS
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC2(CCCCC2Cc2ccccc2)SCCN1
Temperature: 0 °C
Yield: 52.5 %

Procedure:
A mixture of 2-phenylmethyl-1-carboxymethylenecyclohexane (10 g) and 2-aminoethanethiol (10 g) in N,N-dimethylformamide (10 ml) was refluxed for 20 hours under nitrogen atmosphere. The mixture was cooled to 0° C. and diluted with ethyl acetate (100 ml), and the mixture was washed with 1N hydrochloric acid (100 ml), water (100 ml), a saturated aqueous solution of sodium bicarbonte (100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 1-phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]dodecane (6.6 g).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.O1CCOCC1>O>[N+:17]([C:16]1[CH:15]=[CH:14][C:13]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[N:12][CH:11]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CN2CCC(CC2)N1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN3CCC2CC3)nc1

Procedure:
1,4-diazabicyclo[3.2.2]nonane (6.3 g, 50 mmol) was added to a mixture of 2-chloro-nitropyridine (11.9, 75 mmol), and dioxane (250 ml) at 0° C. The reaction mixture was allowed to reach room-temperature. Water (100 ml) was added. The mixture was extracted with dichloromethane (3×50 ml). Chromatography on silica gel with dichloromethane and 10% methanol as solvent gave the title compound as an oil. Yield 8.1 g (65%). Mp. 143-146° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1Cl)(=[O:9])=[O:8].[H-].[Na+].[OH2:23]>>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[OH:23])(=[O:9])=[O:8]
Reactant: O
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 68.6 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(3-methylthiopropyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.0 g, 2.78 mmol), 60% NaH (330 mg, 8.13 mmol) and water (59 μL, 3.25 mmol) were reacted to form the desired product (650 mg, 69%). EI-MS (m/z) 339.86, 341.84 (M−).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH:23]([C:24]#[N:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(Br)c1ccccc1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(C#N)c2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (1.0 g, 3.45 mmol) and bromo(phenyl)acetonitrile (810 mg, 4.13 mmol) in anhydrous DMF was treated with Cs2CO3 (1.46 g, 4.48 mmol) and stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc several times, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel using a gradient elution of 0-20% EtOAc/hexanes. Collection and concentration of the appropriate fractions yielded the title product as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 7.70 (s, 1H), 7.50-7.45 (m, 3H), 7.43-7.29 (m, 7H), 5.08 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H); ES MS (M+1)=406.
Reaction SMILES: [O:1]1CCN=[CH:2]1.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[Li]C(CC)C.CN(C=O)C>C1COCC1>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[CH:2]([OH:1])[O:11][C:10]2=[O:12]
Reactant: C1=NCCO1
Reactant: O=C(O)c1cccc(F)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1OC(O)c2c(F)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a -78° C. solution of the oxazoline derivative (7.8 g, 40.4 mmol), prepared from 3-fluorobenzoic acid in tne usual manner, in THF (50 mL) was added over 15 min sec-BuLi (29 mL of 1.4 M solution). After 30 min, DMF (6.3 mL) was added, and the reaction mixture was stirred at -78° C. for 2 hr. Tne reaction was then quenched with water (10 mL), and the mixture was acidified witn HCl and allowed to stir for 12 hr. The layers were separated, the aqueous layer was extracted with EtOAc, and the combined organic layer was concentrated in vacuo. Tnis material was dissolved in 5% KOH (50 mL), and the base layer was washed with Et2O (2×100 mL) to remove neutrals. The resulting base layer was added to 0° C. solution of concentrated HCl (25 mL), and the resulting cold acidic solution was extracted with EtOAc (3×75 mL). Workup and drying gave a tacky yellow solid (4.4 g) which was recrystallized from CHCl3 to give the title compound (1.97 g, 30%), mp 97°-100° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH2:27])=[CH:25][C:20]=2[O:19][CH2:18]1>>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C:2]3[CH:16]=[CH:15][C:5]4[C:6](=[O:14])[NH:7][C:8]5[C:13]([C:4]=4[CH:3]=3)=[CH:12][CH:11]=[CH:10][N:9]=5)=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: NCc1ccc2c(c1)OCO2
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccc4c(c3)OCO4)ccc12
Yield: 16.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (266 mg, 1.15 mmol) and benzo[d]-[1,3]dioxol-5-ylmethanamine (697 mg, 4.61 mmol) to provide 476 (67 mg, 17% yield) as a white powder. LC-MS (M+H=346, obsd.=346). 1H NMR (400 MHz, DMSO-D6) δ 11.49 (s, 1H), 8.58 (d, J=6.6, 1H), 8.42 (dd, J=1.6, 4.7, 1H), 7.98 (d, J=8.7, 1H), 7.37 (d, J=2.1, 1H), 7.26 (dd, J=4.7, 7.9, 1H), 7.17 (t, J=6.1, 1H), 7.00 (d, J=1.5, 1H), 6.91 (m, 2H), 6.88 (d, J=7.9, 1H), 5.97 (s, 2H), 4.40 (d, J=5.9, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2].Br[CH:13](C(OCC)=O)[C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]1([C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:13]([C:14]([OH:16])=[O:15])[O:3]1)=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)c1cc2ccccc2c(=O)o1
Reaction time: 5 h

Procedure:
A mixture of 2-carboxybenzaldehyde (20.0g), diethyl bromomalonate (20.0g) and anhydrous potassium carbonate (20.0g) in ethyl methylketone (200ml.) was heated under reflux, with stirring, for 5 hours. The cooled mixture was evaporated to dryness and water (300ml.) added to the residue. After extraction with a mixture of ether-chloroform, the organic extracts were washed with water, dried and evaporated to dryness. The residual solid was heated under reflux with a mixture of concentrated hydrochloric acid (360ml.) -- acetic acid (240ml.) for 2 hours. After cooling, the mixture was poured into iced water (1,200ml.). Filtration gave the product as a white solid, m.p. 241°-2° (lit mp. 239°-240°), (Found: C, 62.87; H, 3.39. C10H6O4 requires C, 63.16; H 3.18).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13](=[O:18])[NH:14][CH:15]3[CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([OH:22])=O.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH:30][C:20]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[C:11]([C:13](=[O:18])[NH:14][CH:15]3[CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[CH3:19])[C:2]=1[NH2:1])=[O:22]
Reactant: CC1CCCCC1N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)NC2CCCCC2C)c1N
Yield: 68.7 %

Procedure:
A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCI (28 mg) and HOBt (12 mg) in DMF (0.75 ml) was reacted at room temperature for 24 h. Water (4 ml) was added and the solution was extracted with ethyl acetate (3 mL×2). The organic phase was then washed with water (3 mL), dried over Na2SO4 and evaporated. The residue was purified by preparative TLC plate to give the desired product 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl)-amide (19 mg, 70%). HPLC (4 minute gradient) tR 2.34 min; MS m/z 396.31 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:23]3[CH2:24][CH2:25][CH:20]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:21][CH2:22]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccncc2)nn1
Reactant: C1CCN(C2CCNCC2)CC1
Product: c1cc(-c2ccc(N3CCC(N4CCCCC4)CC3)nn2)ccn1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-pyridin-4-yl-pyridazine and 4-piperidinopiperidine. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (dd, 2H), 8.04 (m, 3H), 7.40 (d, 1H), 4.53 (d, 2H), 2.95 (t, 2H), 2.56 (m, 1H), 2.45 (m, 4H), 1.82 (d, 2H), 1.48 (m, 6H) 1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:20]([CH3:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@H:12]([OH:16])[CH2:13][NH:14][CH3:15])[CH2:7][CH2:6]1.[O:23]=[C:24]1[NH:28][C:27]([C:29]([F:32])([F:31])[F:30])=[C:26]([C:33]([OH:35])=O)[S:25]1>>[Cl:1][C:2]1[C:20]([CH3:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@H:12]([OH:16])[CH2:13][N:14]([CH3:15])[C:33]([C:26]2[S:25][C:24](=[O:23])[NH:28][C:27]=2[C:29]([F:30])([F:31])[F:32])=[O:35])[CH2:7][CH2:6]1
Reactant: CNC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(C)c2Cl)CC1
Reactant: O=C(O)c1sc(=O)[nH]c1C(F)(F)F
Product: Cc1c(Cl)ccc(OC2CCN(C[C@H](O)CN(C)C(=O)c3sc(=O)[nH]c3C(F)(F)F)CC2)c1Cl
Yield: 37.3 %

Procedure:
Prepared as Example 1 using (2R)-1-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]-3-(methylamino)propan-2-ol (0.156 g) and 2-oxo-4-(trifluoromethyl)-2,3-dihydro-1,3-thiazole-5-carboxylic acid (0.096 g) to yield the title compound as a colourless solid (0.091 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][Cl:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[Cl:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCCCl)cc1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(OCC(=O)c2ccc(OCCCl)cc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 27.7 g. (0.1 mol.) of α-bromo-p-(2-chloroethoxy)acetophenone, 12.4 g. (0.1 mol.) of p-methoxyphenol and 13.8 g. (0.1 mol.) of potassium carbonate in 75 ml. of dry acetone is refluxed with stirring for 16 hours. After cooling, the reaction mixture is poured into 500 ml. of water. The product is collected and dissolved in chloroform and the chloroform solution is washed with water, dried (MgSO4) and concentrated to give p-(2-chloroethoxy)-α-(p-methoxyphenoxy)acetophenone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[CH3:8][Si:9]([CH3:24])([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]1[CH2:17][O:16]1>C(O)C>[CH3:24][Si:9]([CH3:8])([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]([OH:16])[CH2:17][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: NCCOCCO
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCCOCCO
Temperature: 70 °C

Procedure:
2-(2-amino-ethoxy)-ethanol (3.83 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess raw material.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19](O)(=[O:21])[CH3:20].O>O1CCOCC1>[C:19]([NH:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12
Reactant: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12

Procedure:
To 2.5 g 10-amino-5,6-dihydro-11H-dibenzo(b,e)azepine-6,11-dione in 50 ml dioxane are added 2 ml anhydrous acetic acid. This mixture is kept at reflux for 2 hours then brought almost to dryness under reduced pressure, and then poured into water, filtered and dried. Yield 2 g (ethanol): melting point 270°-2° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH:5]=O.[N+:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])([O-:20])=[O:19]>C(OC(=O)C)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]([N+:18]([O-:20])=[O:19])=[CH:5][C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])=[CH:3][N:2]([CH3:17])[CH3:1]
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)C[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1ccc(Cl)cc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of 73.1 g (0.29 mol) of the compound of Example 13, 34.0 g (0.29 mol) of methyl nitroacetate and 600 ml of acetic anhydride was stirred and heated at 90°-95° for 45 minutes. The reaction mixture was allowed to cool to room temperature and the crystalline product was collected by filtration. the filtrate was concentrated in vacuo and the residue was slurried with ether (200 ml.) and filtered. The combined materials were washed with ether and dried to give 91.0 g (89%) of red orange crystals, m.p. 193°-197°. Recrystallization from benzenedimethylformamide (6:1,1725 ml) afforded 78.8 g (77%) of product, m.p. 198°-200°.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])[CH3:7].[C:15](O)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][O:10][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:7]
Reactant: CCCCC(CC)CO
Reactant: CC(C)CCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCCCC(C)C

Procedure:
2 g concentrated sulfuric acid were added to a solution of 130 g (1 mol) 2-ethylhexanol and 144 g (1 mol) "isooctanoic acid" (isomeric mixture from Ruhrchemie A. G., Oberhausen) in 300 ml toluene and heated to boiling with water separation until the equimolar amount of water separates (about 2 hours). After cooling it was washed with water and then with 10% sodium bicarbonate solution. The remaining end-product gave after distillation over a 15 cm Vigreux column 230 g (90%) isooctanoic acid-2-ethyl-hexylester as a colorless oil of medium viscosity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([CH2:11][CH:12]=[CH2:13])[CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: C=CCc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To 4-fluoro-1-nitro-2-(2-propen-1-yl)benzene (9.0 g, 50 mmol) in MeOH (100 mL) was added palladium hydroxide on carbon (2 g). The reaction mixture was stirred under H2 (50 psi) at rt overnight. The solution was filtered and concentrated to provide the title compound of step C (7.4 g, 48.3 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 1.10 (t, J=7.5 Hz, 3H), 1.60-1.70 (m, 2H), 2.45 (t, J=7.2 Hz, 2H), 6.55-6.65 (m, 1H), 6.67-6.81 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
A mixture of tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (1 g, 2.25 mmol, 1.00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in 1,4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90° C. for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 700 mg (64%) of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.