Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CS(C)=O.[C-:24]#[N:25].[K+].OS(O)(=O)=O>O.C(OCC)C>[C:24]([C:10]([OH:18])([CH2:9][CH2:8][C:7]1[C:6]([CH3:19])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]=1[OH:11])[CH3:17])#[N:25]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)Oc1c(C)c(C)c(O)c(CCC(C)(O)C#N)c1C

Procedure:
A solution of 2.4 g. (0.1 mol.) of rac. 6-acetoxy-2-hydroxy-2.5,7,8-tetramethylchroman in a total of 200 ml. of dimethyl-sulfoxide was rapidly stirred as 32.5 g. (0.5 mol.) of granular KCN was added thereto by sifting so that a uniformly dispersed suspension was obtained. The resulting suspension was cooled to 15° centigrade as 47.0 ml of 12N aqueous H2SO4 was added over 1.25 hrs. as the internal temp. was maintained at 20 degrees centigrade. Tlc at this point showed a major, slowerrunning spot in addition to trace of starting material. The material was poured into diethylether and H2O. The ether soulutions were washed with water and brine, dried over NaSO4 and stripped of solvent to yield rac. 2-cyano-4-(5-acetoxy-2-hydroxy-3,4,6,-trimethylphenyl)-butan-2-ol as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.O.Cl>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: Cc1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1N
Yield: 78.5 %

Procedure:
4-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrotoluene (5.57 g) and reduced iron powder (9.7 g) were suspended in isopropanol (73 cm3) and water (16 cm3) and concentrated hydrochloric acid (0.83 cm3) added. The mixture was stirred under reflux for 7 hours, cooled slightly and filtered through Hyflo. The filter pad was washed through with hot ethanol. The combined filtrate was evaporated to dryness, dissolved in ethyl acetate and washed with brine. The organic phase was dried (MgSO4), filtered and the filtrate evaporated to dryness to give a brown oil which was purified by flash chromatography (CHCl3) to give 4-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-aminotoluene (4 g) as a pale brown oil. M+ =320
Reaction SMILES: Cl.C1(C(=[N:15][C:16]2[CH:17]=[C:18]([C:22]3[N:23]=[CH:24][N:25]([CH3:37])[C:26]=3[C:27]3[S:36][C:30]4[N:31]=[CH:32][N:33]=[C:34]([NH2:35])[C:29]=4[CH:28]=3)[CH:19]=[CH:20][CH:21]=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[CH:24][N:25]([CH3:37])[C:26]=2[C:27]2[S:36][C:30]3[N:31]=[CH:32][N:33]=[C:34]([NH2:35])[C:29]=3[CH:28]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cn1cnc(-c2cccc(N=C(c3ccccc3)c3ccccc3)c2)c1-c1cc2c(N)ncnc2s1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Reaction time: 0.17 h
Yield: 110.7 %

Procedure:
2M HCl (0.75 mL) was added to a solution of 6-(4-{3-[(diphenylmethylene)amino]phenyl}-1-methyl-1H-imidazol-5-yl)thieno[2,3-d]pyrimidin-4-amine (0.45 g) in THF (15 mL), stirred for 10 mins, then partitioned between water and EtOAc. The aqueous layer was separated, basified to pH9 with concentrated aqueous ammonia, extracted with DCM (3×30 mL), combined organics dried, filtered and concentrated in vacuo to give the title compound as a colourless solid (0.33 g, 100%);
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21](C(NN)=O)[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:29]([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[NH2:29][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([OH:14])=[O:13])[O:23][N:22]=1
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NN)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A solution of tert-butyl(3R)-6-cyclohexyl-3-[3-(hydrazinocarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 71) (1.06 g, 2.76 mmol) in glacial AcOH (10 ml) was treated with 2M HCl (10 ml) and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0° C. before being treated with a solution of NaNO2 (278 mg, in 5 ml H2O) making sure the temperature never rose above 5° C. The reaction mixture was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature before being heated at 85° C. until the evolution of gas a finished. The reaction mixture was neutralised with sat. Na2CO3 solution and extracted with EtOAc. The organic extract was washed with brine and the solvent removed under reduced pressure. The residue was treated with TFA (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×3) and DCM (×3) to afford the title compound as a foam (390 mg, 50%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:48][CH3:49])[C:4]([O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:22][C@H:23]([N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH3:24])=[CH:16][C:17]=2[C:19](=[O:21])[NH2:20])[CH:12]=[CH:11]1)=[O:5])[CH3:2].C(=O)(O)[O-].[Na+]>Cl>[CH2:48]([CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:22][C@H:23]([NH:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH2:36][C:37]([F:39])([F:38])[F:40])[CH3:24])=[CH:16][C:17]=2[C:19](=[O:21])[NH2:20])[CH:12]=[CH:11]1)=[O:5])[CH3:49]
Reactant: CCC(CC)C(=O)OCCCn1ccc2cc(C[C@@H](C)N(CCOc3ccccc3OCC(F)(F)F)C(=O)OC(C)(C)C)cc(C(N)=O)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)C(=O)OCCCn1ccc2cc(C[C@@H](C)NCCOc3ccccc3OCC(F)(F)F)cc(C(N)=O)c21
Yield: 82.4 %

Procedure:
(R)-3-[5-[2-[N-(tert-Butoxycarbonyl)-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl 2-ethylbutyrate (1.56 g) was dissolved in isopropano (10 ml), and concentrated hydrochloric acid (5.0 ml) was added dropwise to the solution under ice-cooling with stirring. After the mixture was stirred for 4 hours at room temperature, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent:methylene chloride/methanol=20/1) and recrystallized from diethyl ether-hexane to give (R)-3-[7-carbamoyl-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indol-1-yl]propyl 2-ethylbutyrate (1.10 g) as white crystals.
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@H:10]([N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:20]([O:19][C:17]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:15]2[CH2:16][NH:8][CH2:9][C@@H:10]12)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]2CNC[C@H]21
Reaction time: 4 h
Yield: 99.6 %

Procedure:
In 130 ml of ethanol was dissolved 3.86 g of (4aS,7aS) -6-benzyl-1-t-butoxycarbonyloctahydropyrrolo[3.4-b]pyridine, and 1 g of 5% palladium-on-carbon was added thereto. While the reaction vessel was heated by a tungsten lamp, hydrogenation was conducted under pressurized hydrogen gas atmosphere of 4 kg/cm2 for 4 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated to give 2.75 g of the titled compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[NH:29][C:28](=[O:30])[C@@H:27]([NH:31]C(OC(C)(C)C)=O)[CH2:26][C:25]2[CH:39]=[C:21]([CH:22]=[CH:23][C:24]=2[OH:40])[C:20]2=[CH:41][C:16](=[C:17]([OH:42])[CH:18]=[CH:19]2)[CH2:15][C@@H:14]([C:43]([NH:45][C@H:46]([C:50]([NH:52][CH2:53][CH2:54][NH2:55])=[O:51])[CH2:47][CH2:48][NH2:49])=[O:44])[NH:13][C:12]1=[O:56])(C)(C)C.[ClH:58]>O1CCOCC1>[ClH:58].[ClH:58].[ClH:58].[ClH:58].[NH2:31][C@H:27]1[CH2:26][C:25]2[CH:39]=[C:21]([CH:22]=[CH:23][C:24]=2[OH:40])[C:20]2=[CH:41][C:16](=[C:17]([OH:42])[CH:18]=[CH:19]2)[CH2:15][C@@H:14]([C:43]([NH:45][C@H:46]([C:50]([NH:52][CH2:53][CH2:54][NH2:55])=[O:51])[CH2:47][CH2:48][NH2:49])=[O:44])[NH:13][C:12](=[O:56])[C@H:11]([CH2:10][CH2:9][CH2:8][NH2:7])[NH:29][C:28]1=[O:30]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCN)C(=O)NCCN)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@@H]1NC(=O)[C@@H](N)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCN)C(=O)NCCN)NC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
15 mg (0.019 mmol) of tert-butyl{3-[(8S,11S,14S)-8-{[((1S)-3-amino-1-{[(2-aminoethyl)amino]carbonyl}propyl)amino]carbonyl}-14-[(tert-butoxycarbonyl)amino]-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-11-yl]propyl}carbamate bis(hydroacetate) (Example 207A) are added into 1 ml of a 4N solution of hydrogen chloride in dioxane and stirred at RT for 20 min. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum.
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)(O)=[O:6]>C1C=CC=CC=1>[Br:3][C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)=[O:6]
Reactant: O=S(Br)Br
Reactant: O=C(O)C12CCCC(C1)C1CCC2C1
Solvent: c1ccccc1
Product: O=C(Br)C12CCCC(C1)C1CCC2C1
Yield: 75.5 %

Procedure:
3 g of thionyl bromide was added dropwise with stirring to 2.0 g (10.3 mmoles) of 1-carboxytricyclo[4.3.1.12,5 ]undecane dissolved in 20 ml of anhydrous benzene at room temperature. The mixture was heated under reflux for 1.5 hours. After cooling, the excess thionyl bromide and benzene were distilled off under reduced pressure. The residue obtained was distilled under reduced pressure to afford 2.0 g (yield: 75.5%) of 1-bromocarbonyltricyclo[4.3.1.12,5 ]undecane having a boiling point of 116° C. (1 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:11]O)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].C(OC(=O)C)(=O)C>CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sc(C=NO)cc1Br
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(Br)c([N+](=O)[O-])s1
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A 5-L, three neck, round bottom flask equipped with a temperature probe, mechanical stirrer, and a reflux condenser was charged with 4-Bromo-5-nitro-thiophene-2-carbaldehyde oxime (Example 25: step c; 441.0 g, 1.76 mol). Acetic anhydride (2.5 L) was added causing an endothermic reaction from 22° C. to 17° C. The resulting yellow slurry was heated to reflux. At 100° C. the reaction became a black solution. After 2 hours at 130° C., TLC analysis (2:1 heptane/EtOAc) showed reaction completion and the heat was removed. The mixture was transferred to a rotary evaporator and concentrated to dryness. The residue was diluted with CH2Cl2 (3 L), and H2O (3 L). The layers were separated and the organic layer was washed with H2O (3 L), dried over MgSO4, and concentrated to give the desired title compound as a tan solid (350.85 g, 86%). 1H-NMR (DMSO): δ 8.3 (1H, s).
Reaction SMILES: [CH2:1]1COCC1.C([Li])CCC.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:1]
Reactant: C1CCOC1
Reactant: COc1ccc(C)cc1C(=O)c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(c1ccccc1)c1cc(C)ccc1OC
Temperature: -78 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a suspension of 7.58 g (21.2 mmole) methyltriphenylphosphoniumbromide in 15 ml abs. THF at room temperature within 10 minutes 17.0 ml (21.2) n-butyllithium (1.25M in n-hexane)are added dropwise. The reddish solution obtained is cooled to −78° C. and then within 15 minutes a solution of 3.70 g (16.3 mmole) 2-methoxy-5-methyl-benzophenone in 5 ml abs. THF is added. Agitation is performed initially for 20 minutes at −78° C. and for a further 8 h at room temperature. Then 80 ml water are added to the reaction mixture and extracted twice with 50 ml diethylether in each case. The purified organic phases are then dried through magnesium sulphate and the solvent is removed. Purification of the raw product obtained takes place by column chromatography on silica gel with toluene as the solvent. 3.03 g (13.5 mmole, 83%) 1-methoxy-4-methyl-2-(1-phenyl-vinyl)-benzene are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[C:25]([C:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])([CH3:29])[CH3:28])#[N:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:25]([C:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=3)[N:13]=2)[CH:23]=1)=[O:34])([CH3:29])[CH3:28])#[N:26]
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 70.3 %

Procedure:
Using N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (92 mg, 0.49 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) and N,N-dimethylformamide (7.0 mL) as starting materials and in the same manner as in Example 318, the title compound (160 mg, 70%) was obtained as a white powder.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])(=[O:21])[CH3:20].CO>CC(C)=O>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C@@H:13]([NH2:18])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])(=[O:21])[CH3:20]
Reactant: CC(C)CC(N)c1ccccc1N1CCCCC1
Agent: CC(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Reaction time: 8 h

Procedure:
A stirred solution of 122 g (0.495 mol) of racemic 1-(2-piperidino-phenyl)-3-methyl-1-butylamine in 1000 ml of acetone is mixed with 93.7 g (0.495 mol) of N-acetyl-L-glutaminic acid. The mixture is refluxed over a vapour bath and methanol is added in batches (a total of about 80 ml) until a clear solution is obtained. After this has been left to cool and stand overnight at ambient temperature, the crystals obtained are removed by suction filtering, washed twice with 200 ml of cold acetone at -15° C. and then dried. The product obtained [98.9 g; melting point: 163-166° C.; [α]D20 =+0.286° (c=1 in methanol)] is recrystallised from 1000 ml of acetone with the addition of 200 ml of methanol, thereby obtaining the (S)-1-(2-piperidino-phenyl)-3-methyl-1-butylamine as the addition salt of N-acetyl-L-glutaminic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][NH:28][C:2]1[C:3]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCCc1nn(C)c2c(Cl)nc(COCC(=O)OCC)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(COCC(=O)OCC)nc12

Procedure:
1.5a 3 g of ethyl (7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethoxy)acetate and 1.9 g of 3-chloro-4-methoxy-benzylamine in 50 ml of dimethylformamide (DMF) are stirred at 60° for 12 hours in the presence of potassium carbonate. After filtration, the solvent is removed, and the mixture is subjected to conventional work-up, giving 4.6 g of ethyl [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetate.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]2[C:9](=[O:17])[NH:8][C@H:7]3[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[ClH:28]>C(OCC)C>[ClH:28].[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[C:10]2[C:9](=[O:17])[NH:8][C@H:7]3[CH2:18][NH:19][CH2:20][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(c(C(F)(F)F)c1)C(=O)N[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: Cl
Solvent: CCOCC
Product: CCc1cc2c(c(C(F)(F)F)c1)C(=O)N[C@H]1CNC[C@H]21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 8-ethyl-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting peak from Part H above, (55 mg, 0.14 mmol) in 2 mL of diethyl ether was added 1 mL of 12 N HCl. The resulting mixture was stirred vigorously for 5 min at ambient temperature and then was concentrated and dried in vacuo. The resulting white solid was triturated twice with diethyl ether and dried in vacuo to afford 40 mg (88%) of the title compound of Example 45 as a white solid. 1H NMR (DMSO-D6): δ 9.83 (broad s, 1H), 9.64 (broad s, 1H), 8.89 (s, 1H), 7.66 (s, 1H), 7.43 (s, 1H), 3.95-3.90 (m, 1H), 3.63-3.58 (m, 1H), 3.51-3.45 (m, 1H), 3.34-3.28 (m, 1H), 3.21-3.10 (m, 2H), 2.73 (q, 2H, J=7.7 Hz), 1.21 (t, 3H, J=7.7 Hz). LRMS (ESI): 285.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[N-:22]=[N+]=[N-].[Na+].O>CN(C)C=O.[C].[Pd]>[CH3:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[NH2:22])=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(N)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.44 g, 4.89 mmol) and sodium azide (0.35 g, 5.37 mmol) in N,N-dimethylformamide (10 mL) was heated and stirred at 100° C. for 30 minutes. The solution was cooled to room temperature and poured into water, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue thus obtained in ethanol (70 mL) was added 10% palladium-carbon (2 g, 50% hydrate), and the mixture was stirred at room temperature for 1 hour under an hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=95:5) to give the title compound (760 mg, 57% yield).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([CH3:33])[CH3:32])[N:25]=3)=[C:18]3[CH2:19][NH:20][CH2:21][CH2:22][N:17]3[N:16]=2)=[CH:11][CH:10]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([CH3:33])[CH3:32])[N:25]=3)=[C:18]3[CH2:19][N:20]([C:35]([O:37][CH3:38])=[O:36])[CH2:21][CH2:22][N:17]3[N:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)Cl
Reactant: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CNCC3)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC(C)C)n3)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Triethylamine (96 mg, 0.948 mmol) was added to a solution of 4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-N-(1-methylethyl)-2-pyrimidinamine (i.e. the product of Step E) (0.150 g, 0.426 mmol) and methyl chloroformate (41.1 μL, 0.178 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 25° C. for 24 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and treated with silica gel (10.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (0:1 to 1:4) as eluant to give 25 mg of the title product, a compound of the present invention, as an off-white solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]1
Reactant: Clc1nc2ccccc2o1
Reactant: CC1(C)CC(OCCO)CC(C)(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)CC(OCCOc2nc3ccccc3o2)CC(C)(C)N1

Procedure:
A mixture of 2-chlorobenzoxazole, 4-(2-hydroxyethoxy)-2,2,6,6-tetramethylpiperidine and K2CO3 in 2-butanone was refluxed for ten hours. The hot mixture was filtered to remove K2CO3. After removal of solvent, the product I was obtained by washing the residue with heptane.
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10]O)[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4].C(N(CC)C(F)(F)C(F)C(F)(F)[F:31])C>C(Cl)Cl>[Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:31])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(S(C)(=O)=O)cc2)[C@@H](CO)N1C(=O)C(Cl)Cl
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)O[C@H](c2ccc(S(C)(=O)=O)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 22.5 °C

Procedure:
(4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIIa) (81 g, 0.2050 moles) in methylene chloride (450 ml) reacts with N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (73.2 g, 0.328 moles) at 95-105° C. for 2-4 hours. Cooling to 20-25° C., quenching with 25% aqueous sodium hydroxide and water (2000 mL) and separation of the methylene chloride layer gives a solution of (4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIIIa) for use as an intermediate for the next step in the process.