Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([O:30]CC2C=CC=CC=2)=[C:16]2[C:21](=[O:22])[N:20]3[CH2:23][C@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[C@@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12].[OH-].[NH4+]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([OH:30])=[C:16]2[C:21](=[O:22])[N:20]3[CH2:23][C@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[C@@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Yield: 78.4 %

Procedure:
A pressure reaction vessel was charged with (4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (950 g), 192 g of palladium on carbon (50% wet), ethanol (9.5 L) and concentrated ammonium hydroxide (124 mL). The mixture was degassed with nitrogen 3 times and then placed under 50 psi of hydrogen until the reaction was complete. The mixture was degassed again with nitrogen and then filtered through Celite. The cake was extracted with refluxing dichloromethane and then filtered again. The combined filtrates were concentrated to a small volume (4 L), azeotroped with ethanol (28.5 L) to a final volume of 9 L. The slurry was filtered and washed with ethanol and dried to produce (4aS,13aR)—N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (616 g, 78.4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.37 (m, 1H), 8.42 (s, 1H), 7.41-7.05 (m, 3H), 4.72-4.53 (m, 4H), 4.05 (m, 1H), 3.86 (m, 1H), 3.70 (m, 1H), 3.16 (m, 1H), 2.88 (m, 2H), 1.92-1.60 (m, 4H).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][O:49][C:50]([N:52]1[CH2:56][CH:55]([C:57]2[C:65]3[C:60](=[CH:61][C:62]([F:66])=[CH:63][CH:64]=3)[NH:59][CH:58]=2)[CH:54]2[N:67]([C:70](=[O:79])[CH:71]([NH2:78])[CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[CH2:68][CH2:69][CH:53]12)=[O:51]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:48][O:49][C:50]([N:52]1[CH2:56][CH:55]([C:57]2[C:65]3[C:60](=[CH:61][C:62]([F:66])=[CH:63][CH:64]=3)[NH:59][CH:58]=2)[CH:54]2[N:67]([C:70](=[O:79])[CH:71]([NH:78][C:11](=[O:13])[CH:9]([N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:14])[CH3:10])[CH:72]3[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77]3)[CH2:68][CH2:69][CH:53]12)=[O:51]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(N)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution containing Boc-N(Me)Ala-OH (76 mg, 0.37 mmol) in anhydrous NMP (4 mL) was cooled to 0° C. HATU (141 mg, 0.37 mmol) and DIPEA (148 mg, 1.14 mmol) were added followed by the addition of crude 51 (172 mg, 0.39 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 255 mg of crude 52 as an off-white-colored foam which was used without further purification. Mass spectrum, m/z [628.5] (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][NH:10]C(=O)OC(C)(C)C)[CH:6]=[N:7][CH:8]=1)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:10][CH2:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1cncc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cncc(CN)c1
Reaction time: 1 h

Procedure:
To tert-butyl (5-cyanopyridin-3-yl)methylcarbamate in CH2Cl2 (10 ml), TFA (3 ml) was added. After 1 h, volatiles were removed on a rotavap under reduced pressure. Crude residue was dissolved in water, basified with 2N NaOH and extracted with CHCl3 (100 ml) to obtain 5-(aminomethyl)nicotinonitrile which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: O=S(=O)(Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1)c1ccc(F)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 3) and 2,4-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: FC1N=C(C([NH:10][NH2:11])=O)C=CC=1.[F:12][C:13]1[C:14]([C:20]([OH:22])=O)=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1.FC1N=C(C(O)=O)C=CC=1>>[F:12][C:13]1[C:14]([C:20]([NH:10][NH2:11])=[O:22])=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: NNC(=O)c1cccc(F)n1
Reactant: O=C(O)c1ncc(F)cc1F
Agent: O=C(O)c1cccc(F)n1
Product: NNC(=O)c1ncc(F)cc1F

Procedure:
3,5-Difluoro-2-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 3,5-difluoro-2-pyridinecarboxylic acid (CAS [745784-04-7], commercially available e.g. from Matrix Scientific, Alfa Aesar or Apollo Scientific) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].C(Cl)Cl>ClCCCl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11])[CH2:2]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC1CN2CCC1CC2
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(OC1CN2CCC1CC2)n1ccnc1

Procedure:
According to Method C, 3-quinuclidol is first reacted with a carbonyldiimidazole (DCI) in an inert solvent (e.g. DCM, 1,2-DCE) at room temperature in order to obtain the corresponding imidazole-1-carboxylic acid 1-azabicyclo[2.2.2]oct-3-yl ester. Then, arylalkylamine (II) is metalated in an inert solvent (e.g. THF) using BuLi and the ester was added at a temperature ranging from 0° C. to room temperature.
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[N:15][CH:14]=2)=[N:8]1.CN(C)C=O.[BH4-].[Na+]>O>[CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[N:15][CH:14]=2)=[N:8]1
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(C(=O)O)n2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CO)n2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 28 mg of 6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carboxylic acid and 1 ml of N,N-dimethylformamide was added 84 mg of N,N′-carbonyldiimidazole, followed by stirring at room temperature for 15 hours. Then, 200 μl of an aqueous solution of 20 mg of sodium borohydride was added thereto and the resulting mixture was stirred. Water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The resulting ethyl acetate solution was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:11]([C:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[I:1]/[CH:2]=[CH:3]/[CH:4]([O:10][C:20]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCC(O)/C=C/I
Product: CCCCCC(/C=C/I)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 14.92 g. (0.0588 mole) of 1-iodo-trans-1-octen-3-ol (Example 955) and 18.2 g. (0.0588 mole) of p-anisyldiphenylmethyl chloride in 165 ml. of dry pryidine is heated at 60°C. for 18 hours under an inert atmosphere. The mixture is cooled and the solvent is evaporated in vacuo. The residue is partitioned between ether and water, and the organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated. The residue is chromatographed upon 300 g. of Florisil packed in hexane and the product is eluted with hexane and 4:1 hexane-benzene the yield a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12]CC)=[C:8]([Cl:15])[C:7]=1[Cl:16])=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:15])[C:7]=1[Cl:16])=[O:5]
Reactant: CCOc1ccc(C(=O)c2ccccc2O)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1O)c1ccc(O)c(Cl)c1Cl

Procedure:
4-(2-Hydroxybenzoyl)-2,3-dichlorophenol was prepared by heating 4-(2-hydroxybenzoyl)-2,3-dichlorophenetole with 3 molar equivalents of aluminum chloride in methylene chloride for 16 hrs.; m.p. 200°-202° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[C:14]3[N:15]=[C:16]([CH3:18])[NH:17][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[C:5](=O)[NH:4][C:3]1=[O:24].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[C:14]3[N:15]=[C:16]([CH3:18])[NH:17][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[C:5](=[S:34])[NH:4][C:3]1=[O:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc2c([nH]1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=O
Product: Cc1nc2c([nH]1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
The title product was prepared from the product of step (iv) (0.1 g) and Lawesson's reagent (0.378 g) according to the method of example 34 step (iv). Purification was by chromatography eluting with 0-5% methanol in dichloromethane followed by reverse phase HPLC using a 40 mm Novapak column eluting with 15-85% methanol in 0.1% aqueous ammonium acetate gradient over 9 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:18])[N:6]2[CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:31][C:32]([N:34]([CH2:41][CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>O>[Cl:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:31][C:32]([N:34]([CH2:41][CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33])[C:5](=[O:18])[N:6]2[CH3:17]
Reactant: Cn1c(=O)[nH]c2c(Cl)nc(-c3ccccc3)nc21
Reactant: CCN(C(=O)CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(Cl)c21)c1ccccc1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a mixture of 6-chloro-7,9-dihydro-9-methyl-2-phenyl-8H-purin-8-one (1.6 g), potassium carbonate (1.0 g) and dimethylformamide (15 ml) is added 2-chloro-N-ethyl-N-phenylacetamide (1.4 g) at room temperature, and the mixture is stirred at the same temperature for two hours. To the reaction mixture is added water, and the precipitates are collected by filtration, washed with water, and purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (1.8 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[C:8](/[CH:12]=[CH:13]/[C:14]3[N:24]=[C:17]4[C:18]([CH3:23])=[N:19][CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[N:9]([CH3:11])[CH:10]=2)=[CH:2]1>CN(C=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[C:8]([CH2:12][CH2:13][C:14]3[N:24]=[C:17]4[C:18]([CH3:23])=[N:19][CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[N:9]([CH3:11])[CH:10]=2)=[CH:2]1
Reactant: Cc1ncc(C)n2nc(/C=C/c3nc(-c4ccoc4)cn3C)nc12
Solvent: CN(C)C=O
Product: Cc1ncc(C)n2nc(CCc3nc(-c4ccoc4)cn3C)nc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of 2-[(E)-2-(4-Furan-3-yl-1-methyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (170 mg, 0.53 mmol) in DMF (13 mL) was added p-toluenesulfonylhydrazide (300 mg, 1.6 mmol). The reaction was stirred for 8 hours at 120° C. The volatiles were removed in vacuo and the residue dissolved in EtOAc (50 mL), washed with saturated sodium bicarbonate solution, brine solution and dried (MgSO4). Filtration, evaporation of the volatiles and purification by column chromatography on silica gel (EtOAc 100%) afforded the title compound (126 mg, 74%). LC-MS: m/z=323.3 (MH+), tR=0.48 minutes, method C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[N:12]O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH2:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(C=NO)c[nH]c2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(CN)c[nH]c2c1

Procedure:
To a mixture of 6-methyl-1H-indole-3-carbaldehyde oxime (0.66 g) and NiCl2.6 H2O (0.97 g) in methanol (60 ml) was added at 22° C. sodium borohydride (3.04 g) in portions. The suspension was filtered and the filtrate evaporated. The residue was partitioned between aqueous NH3 (1%) and ethyl acetate, the organic layer was dried and evaporated to the give the crude title compound as a yellow semi solid (0.68 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:25])([F:24])[CH2:11][CH2:12]N1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.Cl.C(NN)(=O)C1C(=CC=CC=1)C([NH:35]N)=O>C(O)C>[CH2:1]([O:8][CH:9]([NH2:35])[C:10]([F:25])([F:24])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1C(=O)NN
Reactant: O=C1c2ccccc2C(=O)N1CCC(F)(F)COCc1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCC(F)(F)C(N)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
The compound N-(4-benzyloxy-3,3-difluorobutyl)phthalimide (68.5 g, 198.6 mmoles) and hydrazine hydrate (10 g, 200 mmoles) are stirred and heated overnight in ethanol (200 mL) at 90°-100° C. A mixture of concentrated HCl (94 mL) and ethanol (1130 mL) is added, and heating (90°-100° C.) is continued for 1.5 hours. After cooling (ice bath), phthalhydrazide is removed by filtration, and the filtrate is evaporated. The residue is taken up in water and extracted with ether (2×500 mL). After filtration through a membrane filter (Millipore), evaporation of the filtrate yields white crystals. These dissolved in ethanol, the solution is filtered (Millipore organic) and the filtrate is evaporated to yield a residue which crystallizes on addition of ether: 34 g (68%). Evaporation of the ether extracts yields a partially crystalline material (20 g) consisting of starting material. Repetition of the hydrazine cleavage upon this mixture yields a second crop of 4-benzyloxy-3,3-difluorobutylamine (9.1 g). Total: 43.2 g (86.5%).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1)=O.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].C(N(CC)CC)C>C(O)C>[CH3:2][C:1]1[S:3][CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14](=[O:19])[C:13]4[NH:20][CH:21]=[CH:22][C:12]=4[C:11]=3[CH:10]=2)[N:4]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CC(N)=S
Agent: CCC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
17 mg (1.5 mmol) of thioacetamide is added to a suspension of 57 mg (0.15 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 mL of ethanol. The mixture is stirred at 90° C. for 3 hours then the mixture is cooled to room temperature. Triethylamine (2 mmol) is added, then the solvent is evaporated and the product is purified by chromatography on silica (chloroform/methanol 95/5). After drying, 18 mg (34%) of 8-(2-methyl-thiazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]1=2.S(Cl)(Cl)=O.[C:17]([NH2:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].N1C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:26][C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:10]([C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH2:5][CH2:4][C:3]=2[CH:6]=1)=[O:12])=[O:25]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(O)c1ccc2c(c1)CCO2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccccc1NC(=O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
A mixture of 2,3-dihydrobenzo[b]furan-5-carboxylic acid (1.0 g, 6.1 mmol) in thionyl chloride (2.2 mL, 30.5 mmol) is stirred at room temperature for 4 h. The volatiles were removed by evaporation. To a solution of the residue and anthranilamide (750 mg, 5.5 mmol) in CHCl3 (30 mL) is added pyridine (670 □L, 8.3 mmol) and the mixture stirred at room temperature for 18 h. The volatiles were removed by evaporation and the residue is partitioned between EtOAc and 1 N sodium carbonate. The resulting precipitate that formed between the aqueous and organic phases is collected by filtration and dried under vacuum to afford the desired intermediate (1.5 g, 5.3 mmol; 87% yield); ); Rf=0.31 (EtOAc/hexanes, 95/5); mp=230-235° C.; ES MS(M+H)+=283.
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[O:35][N:34]=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[NH2:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:48](=[CH:49][CH:50]=1)[C:29]1=[N:30][O:31][C:32]([C:33]3[C:37]([C:38]([F:39])([F:40])[F:41])=[C:36]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[O:35][N:34]=3)=[C:28]1[CH2:27][CH2:26]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(C)(N)CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 93A, 36 mg, 0.052 mmol) in diethyl ether (3 mL) was added 4 M aqueous solution of HCl (120 μL, 0.480 mmol). The mixture was stirred at room temperature for 30 min. The ether layer was separated and extracted with water (1 mL). The aqueous extract was combined with the aqueous layer in the reaction. The mixture was basified with solid potassium carbonate and extracted with ethyl acetate (4×1.5 ml). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure to give a glassy solid. The individual enantiomers were separated using a Lux-Cellulose-2 column under SFC conditions (20% IPA with 0.1% EA in CO2). Isomer 1 (Preparation 94A, 8 mg), retention time on chiral HPLC, 8.3 min; Isomer 2 (Preparation 94A, 6 mg), retention time on chiral HPLC, 9.3 min. The absolute stereochemistry at the carbon anchoring the secondary alcohol, of Isomer 1 and Isomer 2, was not determined.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:20])[C:8]#[C:9][C:10]2([O:15][Si](C)(C)C)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:15][C:10]1([C:9]#[C:8][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C[Si](C)(C)OC1(C#CC(=O)c2ccncc2)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(C#CC1(O)CCCC1)c1ccncc1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a stirred solution of 1-(pyridin-4-yl)-3-(1-(trimethylsilyloxy)cyclopentyl)prop-2-yn-1-one (1.1 g, 3.8 mmol) in DCM (15 mL) was added PTSA (0.87 g, 4.6 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (2 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 3-(1-hydroxycyclopentyl)-1-(pyridin-4-yl)prop-2-yn-1-one (0.42 g, 51%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[Cl:20][S:21](O)(=[O:23])=[O:22]>>[Br:1][C:2]1[CH:3]=[C:4]([S:21]([Cl:20])(=[O:23])=[O:22])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc2ccncc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(Cl)c1cc(Br)cc2cnccc12
Temperature: 25 °C

Procedure:
7-Bromo-isoquinoline (22.7 g, 109 mmol) is added to a stirred chlorosulfonic acid (230 mL) solution and the resultant mixture is heated at 150° C. under nitrogen for 22 hours. The solution is cooled to ambient temperature and poured very slowly into ice (2 Kg) cooled in a −10° C. bath. While cold, the mixture is adjusted to pH ˜10 with powered Na2CO3 (ca. 200 g) and 5N NaOH. The mixture is extracted with dichloromethane (1 L×2). The combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to give 16.3 g (crude yield 49%) of 7-bromo-isoquinoline-5-sulfonyl chloride as a tan solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11]1[N:12](C2CCCCO2)[C:13]2[C:18]([N:19]=1)=[C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:16]=[C:15]([Cl:26])[N:14]=2)[CH3:10])C)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:26][C:15]1[N:14]=[C:13]2[C:18]([N:19]=[C:11]([CH:9]([NH:7][CH3:6])[CH3:10])[NH:12]2)=[C:17]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:16]=1
Reactant: CC(c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1)N(C)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CNC(C)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of {1-[2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (316 mg, 0.66 mmol) and p-toluenesulfonic acid monohydrate (30 mg) in methanol was stirred at room temperature for 3 h, then allowed to stand for 56h. The reaction mixture was concentrated in vacuo to a small volume, then DCM (3 mL) and trifluoroacetic acid (3 mL) were added and the reaction mixture was stirred for 4.75 h at RT. Another portion of trifluoroacetic acid (3 mL) was added and stirring was continued for 2 h. The mixture was concentrated in vacuo and the resulting residue was triturated three times with diethyl ether. The resulting solid was partitioned between a 10% solution of methanol in DCM and aqueous sodium bicarbonate. The phases were separated, and the aqueous phase was extracted four times with a 10% solution of methanol in DCM. The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to give [1-(2-Chloro-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-methyl-amine (0.19 g, 97%). LCMS RT=1.68 min, [M+H]+=297