Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:13]2[CH2:17][CH2:16][C@H:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1.[ClH:26]>O1CCOCC1>[ClH:26].[C:1]1([C@@H:13]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
To a mixture of tert-butyl (1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (1.57 g, 4.59 mmol) in 1,4-dioxane (45 mL) was added HCl (4 M in 1,4-dioxane, 8.0 mL, 32.0 mmol). The reaction mixture was then heated at about 60° C. After about 2 h, the reaction mixture was cooled to ambient temperature, filtered, while washing with Et2O (50 mL) and the solid was dried in a vacuum oven overnight at about 60° C. to give (1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (1.38 g, 95%): LC/MS (Table 2, Method a) Rt=0.74 min; MS m/z: 243 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12]C)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][C@@:18]2([CH:28]([NH2:31])[CH2:29][CH3:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(O)C.Cl>O>[NH2:31][CH:28]([C@@:18]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:17][C@@H:16]2[CH2:21][C@H:19]1[CH2:20][CH:15]2[O:14][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]2)[CH2:29][CH3:30]
Reactant: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2Oc1cc2ccnc(OC)c2cc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2Oc1cc2cc[nH]c(=O)c2cc1Cl
Temperature: 100 °C
Yield: 100.4 %

Procedure:
35 mg of 1-[(1S,2S,4S)-5-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-2-phenyl-bicyclo[2.2.1]hept-2-yl]-propylamine (90) were dissolved using 1 mL of 2-propanol and 1 mL of a 1N aqueous HCl-solution. The mixture was heated to 100° C. for 1 h under microwave irradiation. Afterwards, 20 mL of water were added and the mixture freeze dried. The residue was once again treated with 20 mL of water and freeze dried to yield 34 mg of the desired product as its hydrochloride. Rt=0.75 min (Method 18). Detected mass: 423.2 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
To 100 mL of chloroform is added 4-chlorobenzeneacetic acid (17 g, 0.1 mol) and 24 g (0.2 mol) of thionyl chloride. Reflux the reaction mixture for 3 hours and remove the solvent in vacuo to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C@@H:8]1[C@@H:16]2[C:17]3[CH:18]=[CH:19][C:20]([O:25]S(C)(=O)=O)=[CH:21][C:22]=3[CH2:23][CH2:24][C@H:15]2[C@H:14]2[C@@H:10]([C:11](=[O:30])[CH2:12][CH2:13]2)[CH2:9]1>C1COCC1>[F:7][C@@H:8]1[C@@H:16]2[C:17]3[CH:18]=[CH:19][C:20]([OH:25])=[CH:21][C:22]=3[CH2:23][CH2:24][C@H:15]2[C@H:14]2[C@@H:10]([CH:11]([OH:30])[CH2:12][CH2:13]2)[CH2:9]1
Reactant: CS(=O)(=O)Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(=O)[C@H]3C[C@H](F)[C@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(O)[C@H]3C[C@H](F)[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg of lithium aluminum hydride is added to the solution of 90 mg of 11β-fluoro-3-mesyloxy-gona-1,3,5(10)-trien-17-one in 10 ml of anhydrous THF, and it is stirred for 2 hours while being cooled with ice, for 16 hours at room temperature and for 1 hour under reflux. After cooling, it is mixed with saturated common salt solution, extracted with ethyl acetate, the organic phase is dried with sodium sulfate, and the solvent is concentrated by evaporation. The residue is chromatographed on silica gel with hexane and ethyl acetate, 42 mg of 11β-fluoro-gonadiol (59% of theory) is isolated as a solid foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])(=O)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([CH2:8][Cl:13])=[C:6]([F:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1c(F)cccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Fc1cccc(Cl)c1CCl
Reaction time: 3 h

Procedure:
The starting material may be prepared as follows: A mixture of 98 g (0.678 mole) of 6-chloro-2-fluorotoluene, 91.5 g (0.678 mole) of sulfuryl chloride and 0.2 g of dibenzoyl peroxide is stirred for 3 hours at 100°-110° C. and then distilled, affording 6-chloro-2-fluorobenzyl chloride with a boiling point in the range from 78°-82° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-]>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)=[CH:3][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Oc3ccccc3)c2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The compound (500 mg) prepared in Step 1, N-Boc-piperazine (500 mg) and tassium carbonate (2.0 g) were dissolved in dimethylformamide (3 ml), and stirred at 90° C. for 2 hours. The dimethylformamide of the mixed solution was removed by distillation under reduced pressure, and extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, and water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The solvent-removed mixture was purified by column chromatography to obtain a yellow target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]([OH:23])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]([O:23][CH2:29][CH3:30])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)Cc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12

Procedure:
1-(4-Nitrophenyl)isoquinoline-5-acetic acid (5.0 g) was dissolved in 300 ml of ethanol, and 4.0 ml of conc. sulfuric acid was added. The mixture was heated for 6 hours. After the reaction, the solvent was distilled off. Benzene was added to the residue. It was washed in water and dried. The solvent was distilled off, and the residue was recrystallized from ethanehexane to afford 4.8 g of ethyl 1-(4-nitrophenyl)isoquinoline-5-acetate as colorless needles having a melting point of 89.5° to 90.5° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27].O>CN(C=O)C>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][N:2]=2)[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cnccn2)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cnccn2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
A mixture of 5-pyrazin-2-yl-1H-pyrimidine-2,4-dione hydrochloride (Prep125, 2.19 mmol), and K2CO3 (302 mg, 2.19 mmol) in DMF (20 ml) was stirred 30 minutes at room temperature. 90% 3-Bromo-1,1dimethoxy-propane (365 μl, 2.41 mmol) was added in two portions during 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-0.2) to give 221 mg of the title compound (35% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:23][C:22]2[N:18]([C:14]3[CH:13]=[C:12]([C:10]4[CH2:9][C:8](=[O:25])[NH:7][C:6]5[CH:26]=[C:27]([C:28]([F:29])([F:31])[F:30])[C:3]([N:2]([CH3:32])[CH3:1])=[CH:4][C:5]=5[N:11]=4)[CH:17]=[CH:16][CH:15]=3)[N:19]=[N:20][CH:21]=2)[CH2:39][CH2:38]1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: NC1CC1
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 17) (444 mg, 1.0 mmol) by treatment with SOCl2 (3 eq.) and cyclopropyl amine (10 eq.) as described in Example 45. Obtained as a yellow solid (248 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([O:16][CH3:17])[CH:13]=3)[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]N(C=O)C.O(C)[Na].IC>O.C1C=CC=CC=1>[CH3:21][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][C:14]2[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([O:16][CH3:17])[CH:13]=2)[C:8]1=[O:20]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reactant: CN(C)C=O
Agent: CO[Na]
Solvent: c1ccccc1
Solvent: CI
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Phenyl-5-methoxy-6,7-dichloro-1-indanone, 50.84 g. is dissolved in 700 ml. dry DMF and 700 ml. benzene in a 3-liter flask equipped with a nitrogen inlet, air condenser and hopper for NaOCH3. The reaction mixture is cooled in ice-water and 103 ml. of iodomethane is added. NaOCH3, 13.5 g., is added portion wise from the hopper over 3/4 of an hour. After stirring for 1/2 hour in an ice-water bath, the reaction mixture is added to water, (4 liters), and extracted with benzene. The benzene layer is separated dried over molecular sieves and concentrated to dryness to give 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone, mp 164°-5°C. after recrystallization from benzene-cyclohexane, 1:2.
Reaction SMILES: C([O-])(O)=[O:2].[Na+].[OH:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[Na+].[Br-].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1.CC(O)C>[C:17]([O:16][C:14]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH:8]1[C:7]([OH:2])=[O:6])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCOCC1CO
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Br-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Saturated aqueous NaHCO3 (15 mL) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.09 g, 5.0 mmol) (Organic and Bio-Organic Chemistry (1972-1999); (1985); 2577-2580, WO 2006/114606 and US 2010/210640) in acetone (50 mL) at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added for 20 min at 0° C. After addition, the reaction mixture was allowed to room temperature (RT) and further maintained overnight. 2-Propanol (3 mL) was added and the resulting solution was stirred at RT for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL), acidified with 6N HCl and extracted with EtOAc (5×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to give title compound as a white solid (760 mg). (M−H)−229.9.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:24]O>>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:24])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)C(F)(F)F)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1C

Procedure:
2.33 g (8.56 mmol) of 3-fluoro-2-methyl-4-(pentafluoroethyl)benzoic acid were introduced into 30 ml of methanol and admixed with 2 ml of concentrated sulfuric acid. The mixture was subsequently heated at reflux until a check by HPLC indicated full conversion. The contents were freed from the solvent on a rotary evaporator, and the residue was taken up in water. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed once with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried and freed from the solvent. The residue obtained was 2.1 g of clean product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16](I)[N:11]3[N:10]=2)[CH:8]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:21][C:22]1[N:23]=[CH:24][C:25]([C:16]2[N:11]3[C:12]([S:13][C:9]([C:7]4[CH:8]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:4]([NH2:18])=[N:5][CH:6]=4)=[N:10]3)=[N:14][CH:15]=2)=[CH:26][CH:27]=1
Reactant: Nc1ncc(-c2nn3c(I)cnc3s2)cc1C(F)(F)F
Reactant: OB(O)c1ccc(F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2nn3c(-c4ccc(F)nc4)cnc3s2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 53 %

Procedure:
3-(trifluoromethyl)-5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyridin-2-amine (0.100 g, 0.243 mmol, 1 eq) was dissolved in dioxane (1.5 mL), then 2-fluoropyridine-5-boronic acid (0.055 g, 0.389 mmol, 1.6 eq) was added followed by 2M aq. Na2CO3 (0.5 mL, 4 eq). The suspension was degassed (N2, 15 min) and equipped with an argon balloon. Pd(Ph3P)2Cl2 (0.043 g, 0.061 mmol, 0.25 eq) was quickly added, and the reaction flask was placed in a pre-heated bath (115° C.). After stirring at reflux temperature for 3 h the mixture was cooled to RT and concentrated. The residue was suspended in EtOAc and water, and the clear water phase was removed. The remainder was concentrated to dryness and triturated with Et2O, filtered off, washed with Et2O and dried in vacuo to afford the desired product (0.049 g, 53%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.14 min, [M+H]+ m/z 381.0; 1H-NMR (DMSO-d6): δ=8.93 (1H ,bs), 8.84 (1H, bs), 8.67-8.58 (1H, m), 8.24 (1H, bs), 7.92 (1H, s), 7.42-7.34 (3H, m) ppm
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:1]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[CH3:8])=[O:25])=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCCCC1=N
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)Nc1ccc(OCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to the free base in benzene in the usual manner. After drying over K2CO3 and filtering, a benzene solution of 0.05 mole of p-benzyloxyphenylisocyanate is added dropwise with stirring. After addition is complete, further stirring is continued for about 6 hours at room temperature. The benzene is evaporated in vacuo and the solid residue is recrystallized from methanol to give the product 1-(4-benzyloxyphenyl)-3-(1-methyl-2-piperidylidene)urea.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=3)[CH:15]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:33]([F:34])([F:35])[C:23]1[CH:22]=[C:21]([O:20][CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:37])=[O:5])[CH2:18][CH2:17]3)[CH:26]=[CH:25][C:24]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(COc3ccc(-c4ccccc4)c(C(F)(F)F)c3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCN1CCc2cc(COc3ccc(-c4ccccc4)c(C(F)(F)F)c3)ccc2C1
Temperature: 25 °C

Procedure:
To a solution of 3-[6-(2-trifluoromethyl-biphenyl-4-yloxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid tert-butyl ester (35 mg, 0.068 mmol) in CH2Cl2 (1 mL) is added TFA (1 mL). The mixture is stirred at room temperature for an hour. All the solvents are evaporated. The mixture is purified by reverse phase preparative LC/MS to give 3-[6-(2-trifluoromethyl-biphenyl-4-yloxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[S:16]([Cl:19])(=[O:18])=[O:17])[CH2:4]1)[CH3:2].[CH2:20](N1CCC[C@H]1CCC1C=CC=C(F)C=1)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:20][C@H:4]1[CH2:5][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:16]([Cl:19])(=[O:17])=[O:18])[CH3:2]
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Reactant: CCN1CCC[C@H]1CCc1cccc(F)c1
Product: CCN1CCC[C@H]1CCc1cc(F)ccc1S(=O)(=O)Cl

Procedure:
Prepared by proceeding in a similar manner to intermediate 96, starting from (R)-1-ethyl-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (intermediate 231).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](O)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.P(Cl)(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([S:2][CH3:1])=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CSc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A mixture of 4-(methylthio)-2,6-dinitrophenol (1 g.), phosphorus oxychloride (7.5 ml.), and dimethylformamide (1 ml.) is heated at 90°-100° C. for four hours. The cooled reaction mixture is poured into ice-water. The resulting product is collected by filtration.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[O:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:18][N:17]=[CH:16]1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[O:15]1[C:19]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH:6]4[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]4)=[CH:13][CH:12]=3)(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[CH:18][N:17]=[CH:16]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(-c4cnco4)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
The crude 4-(1-propyl-azetidin-3-yl)-phenylamine (40 mg, 0.21 mmol) was dissolved in CH2Cl2/pyridine 9:1 (10 ml) and 4-oxazol-5-yl-benzenesulfonyl chloride (51 mg, 0.21 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 and washed successively with 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 95:5) to afford the title compound (30 mg, 36%) as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[C:23]1[C:32]2[N:31]=[CH:30][CH:29]=[N:28][C:27]=2[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:33]([C:26]3[C:27]4[N:28]=[CH:29][CH:30]=[N:31][C:32]=4[C:23]([C:17]4[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=4[CH3:15])=[CH:24][CH:25]=3)=[O:34])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)nc2)c2nccnc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt, using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71). Title compound: ESI-MS: 453.1 [M+H]+; tR=3.55 min (System 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=O.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[N:24]=[N:23][C:22]([C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH:14]3[CH2:16][CH2:15]3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1)=[O:8]
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: COC(=O)c1ccccc1C(=O)O
Product: COC(=O)c1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 14, making variations only as required to use phthalic acid monomethyl ester in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a light yellow solid (97% yield). 1H NMR (300 MHz, CDCl3) δ 8.02-8.06, 7.96, 7.88, 7.60, 7.48, 7.30, 6.98, 3.72-4.02, 3.54, 3.33, 1.49, 0.74, 0.45, 0.08. MS (ES+) m/z 438 (M+1).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:10][CH2:9][C@H:8]1[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5][C@@H:4]1[N:1]=[N+:2]=[N-:3])(=[O:22])[CH3:21]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 2 h

Procedure:
To a solution of 3'-azido-3'-deoxythymidine (AZT) 20 g) in pyridine (50 mL) at ambient temperature, acetyl chloride (2.1 equivalents) was added. The reaction was stirred for two hours and kept at 0° at 5° C. for 20 hours. It was poured onto ice water with stirring. The aqueous phase was decanted. The oily product was dissolved in ethyl acetate and extracted with water (5 times), 0.5 N hydrochloric acid, water (2x), and dried over magnesium sulphate. The solution was filtered and evaporated in vacuo. The residual oil was dissolved in chloroform, applied to a silica gel column, and flash chromatographed using 2% methanol in chloroform. Fractions with product were evaporated and the oil was chromatographed again using ethyl acetate:hexane (6:4 v/v). Fractions with product were evaporated in vacuo to give 5'-O-acetyl-3'-azido-3'-deoxythymidine as a white solid.