Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:21])[C@@H:10]([CH:11](Br)[C:12](=O)CBr)[C@H:9]1[C:17]([O:19][CH3:20])=[O:18].O>O1CCCC1>[CH3:7][C:8]1([CH3:21])[C@@H:10](/[CH:11]=[CH:12]\[C:1]([OH:3])=[O:4])[C@H:9]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1[C@H](C(Br)C(=O)CBr)C1(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Reaction time: 1.5 h

Procedure:
1 ml of a 1N solution of potassium carbonate was placed under an inert gas atmosphere and then a solution of 0.342 g of methyl (1R,cis) 2,2-dimethyl-3-(1,3-dibromo-2-oxopropyl)-cyclopropane-1-carboxylate in 1.5 ml of tetrahydrofuran was added at about +5° C. The mixture was stirred for 90 minutes and then the temperature was allowed to rise to 20° C. and stirring was continued for 4 hours. Water was added and extraction was carried out with methylene chloride. The organic phase was dried and the solvent was evaporated. The residue was chromatographed on silica, eluting with a methylene chloride - ethanol mixture (97-3) to obtain 0.046 g of the expected product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=O)=O.C1CCN2C(=NCCC2)CC1.[CH2:45]([N:47]=[C:48]=[O:49])[CH3:46]>C1COCC1.C([O-])(O)=O.[Na+]>[C:30]([C:29]([CH3:33])([CH3:32])[C:21]1[CH:22]=[C:23]2[C:28](=[C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2][CH3:1])=[CH:6][CH:7]=3)[C:48]([NH:47][CH2:45][CH3:46])=[O:49])[CH:20]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)#[N:31]
Reactant: CCN=C=O
Reactant: CC(C)(C#N)c1cc(-c2cccc(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)N(Cc1cccc(-c2cc(C(C)(C)C#N)cc3cccnc23)c1)c1ccc(SC)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To solution of 2-(8-{3-[(4-methanesulfonyl-phenylamino)-methyl]-phenyl}-quinolin-6-yl)-2-methyl-propionitrile from EXAMPLE 36 (Step 1) (1.0 eq) in 2 mL of THF (0.17M) was added DBU (1.1 eq) and ethyl-isocyanate (8.3 eq). The resulting mixture was stirred at 60° C. for 12 h, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 4:1) afforded a contaminated sample of the desired compound as a oil. It was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[C:12]1([CH2:18][C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:19](=[O:20])[CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: CCOC(=O)Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C(C#N)C(=O)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
To a mixture of [3-(methyloxy)phenyl]acetonitrile (2.0 g, 14 mmol) and ethyl phenylacetate (2.8 g, 17 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 10.2 mL, 27 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3-(methyloxy)phenyl]-3-oxo-4-phenylbutanenitrile as a brown oil (0.8 g, 3.4 mmol, 38% yield), MS (EI) for C17H15NO2: 266 (MH+).
Reaction SMILES: N1C=C[CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10]CC[CH2:7]1>>[CH3:10][N:6]([CH3:7])[CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH3:3]
Reactant: c1cn[nH]c1
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Product: C[C@H](CN(C)C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N,N dimethyl-1,2-propanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.FC(F)(F)C(F)(F)C(F)(F)C([O:18][C:19](=O)[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:8][C:19](=[O:18])[C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)F

Procedure:
5-Chloro-3-nitro-2-aminopyridine is reacted with heptafluorobutyric anhydride to obtain 5-chloro-3-nitro-2-(heptafluorobutyramido)pyridine which when hydrogenated yields 6-chloro-1-hydroxy-2-(heptafluoro-n-propyl)-1H-imidazo(4,5-b)pyridine.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][Al](C)C>CN(C=O)C.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>[Cl:12][C:4]1[N:3]=[C:2]([CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 70 °C
Yield: 44.4 %

Procedure:
To a pressure vessel, a degassed solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (3.0 g, 14.4 mmol) (R. J. Rousseau and R. K. Robins J. Heterocyclic Chem. 2, 1965, 196) and tetrakis(triphenylphosphine)palladium(0) (1.67 g, 1.44 mmol) in DMF (45 mL) was stirred at room temperature. To this mixture was added dropwise a solution of trimethylaluminium (7.93 mL, 15.8 mmol, 2M in toluene). The resulting mixture was sealed and heated at 70° C. for 3 hours. The reaction mixture was poured into ice/water (800 mL). The organic material was extracted with EtOAc (5×200 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica gel dry column using EtOAc:Hexane gradient (1:9) to (3:7) to afford the desired compound as a yellow solid (1.20 g, 45%), HPLC: 99% (220 nm), LCMS (+ESI, M+H+) m/z 188, IR (KBr, cm−1) 3431, 3310, 3172, 1653, 1506, 1264; 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 6.57 (br s, 2H), 2.63 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([CH2:14][CH2:15][CH:16]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S([CH2:34][N+:35]#[C-:36])(C1C=CC(C)=CC=1)(=O)=O.[C-]#[N:38].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([CH2:14][CH2:15][C:16]2[NH:38][CH:34]=[N:35][CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(CCC=O)(C2CCCCC2)CC1
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCc2cnc[nH]2)(C2CCCCC2)CC1
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of 4-cyclohexyl-4-(3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester, 10, (300 mg, 0.93) in ethanol (10 ml) is treated with tosylmethyl isocyanide (tosMIC) (176 mg, 0.93 mmole) and sodium cyanide (6 mg) at room temperature for three hours. The solvent is removed under reduced pressure and ammonia in methanol (2M, 10 ml) added. The mixture is stirred in a sealed tube overnight. The reaction mixture is then concentrated under reduced pressure and the residue taken up in chloroform, washed with aqueous sodium bicarbonate, brine, then dried with sodium sulfate and concentrated to a red oil. The residue is purified over silica (methylene chloride:methanol=15:1, Rf=0.58) to afford 141 mg (42% yield) of the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2OC)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[C:19]([CH:26]=[O:27])=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.[C:28](=O)([O-])[O-:29].[K+].[K+]>CC#N>[CH3:25][O:24][C:21]1[CH:20]=[C:19]([CH:26]=[O:27])[C:18]([O:17][CH2:2][C:3]2[C:4]([C:9]3[CH:10]=[CH:11][C:12]([O:29][CH3:28])=[CH:13][CH:14]=3)=[N:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][N:22]=1
Reactant: COc1cc(C=O)c(O)cn1
Reactant: COc1ccccc1-c1ncccc1CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ncccc2COc2cnc(OC)cc2C=O)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(2-methoxyphenyl)pyridine (234 mg, 1.00 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (153 mg, 1.00 mmol, 1.00 equiv), and potassium carbonate (278 mg, 2.01 mmol, 2.00 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um; 19*150 mm; mobile phase, water with 0.1% TFA and MeCN (20.0% MeCN up to 50.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 265.1 mg (46%) of 2-methoxy-5-[[2-(4-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([O:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1.C(N(CC)C(C)C)(C)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([O:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 0.4 g, 1.46 mmol) in DMF (2 mL), was added (3R,4S)-benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate (enantiopure Intermediate 12, 0.40 g, 1.60 mmol) and N,N-diisopropylethylamine (0.3 mL, 3.1 mmol). The mixture was heated at 85° C. overnight. After cooling, the mixture was added water, stirred for 3 h, filtered, rinsed with water, and dried to give (3R,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methoxypyrrolidine-1-carboxylate (0.62 g, 87% yield) as a brown solid. MS (ES+) m/z: 487.1, 488.3 (M+H); LC retention time: 3.82 min (analytical HPLC Method).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[F:6][C:7]([F:33])([F:32])[C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](Cl)=[N:18][C:17]=2[O:26][CH2:27][CH:28]([F:30])[F:29])[CH2:10][CH2:9]1.C1COCC1>CO>[F:32][C:7]([F:6])([F:33])[C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[N:18][C:17]=2[O:26][CH2:27][CH:28]([F:30])[F:29])[CH2:12][CH2:13]1
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F
Reactant: NCC(F)F
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1OCC(F)F
Reaction time: 20 h

Procedure:
2,2-Difluoroethylamine (0.18 mL, 2.53 mmol) is slowly added to a mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-chloro-5-nitro-2-(2,2-difluoroethoxy)-nicotinic acid amide (prepared according to WO2010/34799, 1.00 g, 2.3 mmol) and 10 mL THF at 0° C., 2 mL MeOH is added and it is stirred for 20 h. The mixture is concentrated and the solid residue is washed with water and dried. Yield: 0.96 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CCl)ccn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)ccn1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 4-chloromethyl-2-methyl-pyridine (described in WO 2006023707) gave the title compound. ES-MS m/e (%): 504.2(M+H+).
Reaction SMILES: [N+]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[C:5]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:11]1([C:9]2[O:10][C:6]3[C:7]([N:8]=2)=[CH:17][CH:18]=[C:4]2[C:5]=3[CH2:19][C:20](=[O:22])[NH:21]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1c([N+](=O)[O-])ccc2nc(-c3ccccc3)oc12
Reactant: O=S(=O)(O)O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(ccc3nc(-c4ccccc4)oc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (6-nitro-2-phenyl-benzoxazole-7-yl)-acetonitrile (66 mg 0.23 mmol) (Starting Material 7) was suspended in concentrated H2SO4/H2O (1/1, 2 mL)) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (3 mL) heated at reflux was added excess zinc dust (120 mg, 1.85 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-oxazolo[5,4-e]indol-7-one. (Yield 17 mg, 30%)
Reaction SMILES: C[O:2][C:3](=O)[C@H:4](C)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1CCCCC1.[H-].C([Al+]CC(C)C)C(C)C.[CH:31]([Mg]Br)=[CH2:32].[C:35]1([CH3:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:5][C@@H:4]([CH2:41][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH:3]([OH:2])[CH:31]=[CH2:32])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccccc1
Reactant: COC(=O)[C@H](C)N(C(=O)OC(C)(C)C)C1CCCCC1
Reactant: C=C[Mg]Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a stirred -78° C. solution of Boc-cyclohexylalanine methyl ester (10.2 g, 35.8 mmol) in dry toluene (60 ml) was added diisobutylaluminum hydride (34 ml of a 1.5M solution in toluene). After 30 min., vinyl magnesium bromide (108 ml of 1M solution in tetrahydrofuran (THF)).was added. After stirring for 15 hours at 0° C., the mixture was carefully quenched with methanol, treated with Rochelle salts (22 ml of saturated aqueous solution in 140 ml H2O), and filtered. After extracting the solids 5 times with ethyl acetate, the extracts and filtrate were combined and the organic phase was washed with brine, dried, filtered and evaporated to an oil (10.2 g). Chromatography on silica gel eluting with hexane/ethyl acetate mixtures provided 6.1 g (60%) of the desired product.
Reaction SMILES: [Cl-].[CH3:2][CH:3]1[NH2+:8][CH:7]([CH3:9])[CH2:6][O:5][CH2:4]1.Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>>[CH3:9][CH:7]1[N:8]([CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:18])[CH:3]([CH3:2])[CH2:4][O:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC1COCC(C)[NH2+]1
Agent: [Cl-]
Product: CC1COCC(C)N1CCN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared by a similar method to Preparation 6 from 3,5-dimethyl-1,4-oxazinan-4-ium chloride [see Preparation 10] and N(2-bromoethyl) phthalimide. The crude produce was purified by column chromatography on silica gel eluting with a solvent system of 8:1, by volume, hexane:ethyl acetate to afford 2-[2-(3,5-dimethylmorpholino)ethyl]-1H-isoindole-1,3(2H)-dione (455 mg) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(Cl)(Cl)Cl.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccc2OC)CC1)CCC3
Yield: 56 %

Procedure:
Method A (40 h at 50° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-methoxyphenyl)piperazine hydrochloride; yield 56%; fusion point 177°-178° C. (from chloroform and ethanol). Fumarate: method E; yield 87%; fusion point 173°-174° C. (from acetone).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:25]([O:27]CC)=O)=[N:15][N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:10]=3[C:9]2=[O:30])=[CH:4][CH:3]=1.O.[NH3:32]>C(O)CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:25]([NH2:32])=[O:27])=[N:15][N:16]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[C:10]=3[C:9]2=[O:30])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
Solvent: OCCO
Solvent: O
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(I)cc2)CC3)cc1
Temperature: 85 °C

Procedure:
Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate from Part B of example 6 (3.0 g, 5.8 mmol) was suspended in 8% NH3 in ethylene glycol (30 mL) in a 100 mL pressure tube. The mixture was heated at 85° C. for 18 hours. Water was added, and the precipitate was filtered and washed with water. The crude product was dried under vacuum to afford 3.2 g of final product. MS (ES+): 489.2 (M+H)+. 1HNMR (DMSO-d6) δ 7.72-7.68 (m, 3H), 7.49-7.41 (m, 3H), 7.15 (d, 2H), 6.97 (d, 2H), 4.00 (t, 2H), 3.77 (s, 3H), 3.16 (t, 2H) ppm.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4]4)=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:33][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1S,3S)-3-aminocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f64) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH4+:1].[Cl-:2].C[Al](C)C.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([CH2:18][C:19]#[N:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[ClH:2].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([CH2:18][C:19]([NH2:1])=[NH:20])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: N#CCC1(c2ccccn2)CCCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cl
Product: N=C(N)CC1(c2ccccn2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a stirred suspension of NH4Cl (1.05 g, 19.355 mmol) in dry toluene (15 mL) was added tri-methyl aluminum (2M) (5.2 mL, 10.323 mmol) at 5° C. The reaction mixture was warmed to room temperature and the reaction mixture was stirred for 2 h. A solution of (1-pyridin-2-yl-cyclopentyl)-acetonitrile (434) (1.2 g, 6.45 mmol) in toluene (5 mL) was added to above reaction mixture and the reaction mixture was stirred for 14 h at 100° C. After completion of the reaction, the reaction mixture was quenched with a suspension of silica gel (5 g) in chloroform (30 mL) and reaction mixture was stirred for half an hour at room temperature. It was filtered through a sintered funnel and the residue (silica gel) was washed with methanol (30 mL). The combined filtrate was concentrated and the resulting crude mass was stirred with 10% methanol in dichloromethane (100 mL). The thus generated suspension was filtered and the filtrate was concentrated under reduced pressure to get 2-(1-pyridin-2-yl-cyclopentyl)-acetamidine hydrochloride (435) (1.05 g, 80%) as a white solid.
Reaction SMILES: [C:1]12([CH:11]([OH:37])[CH2:12][O:13][C:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C@H:25]5[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[NH:16][N:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].O1CCCC1.Cl>O>[C:1]12([CH:11]([OH:37])[CH2:12][O:13][C:14]3[CH:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([C@H:25]5[CH2:26][CH2:27][C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]5)=[CH:23][CH:24]=4)[NH:16][N:15]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Reaction time: 8 h

Procedure:
A scintillation vial was charged with the product from Example 1G (18 mg, 0.036 mmol), lithium hydroxide monohydrate (5 mg, 0.12 mmol) and a mixed solvent (2 mL of tetrahydrofuran, 1 mL of H2O). The reaction vessel was placed in a shaker at room temperature overnight. After this time the mixture was acidified with 10% HCl, concentrated, and purified via RP-HPLC (Preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7 μM 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min.) to provide the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (m, 2H), 1.42-1.86 (m, 19H), 1.94 (m, 3H), 2.14 (d, J=7.01 Hz, 2H), 2.47 (m, 1H), 3.89 (dd, J1=10.38 Hz, J2=7.94 Hz, 1H), 4.24 (dd, J1=10.68 Hz, J2=2.74 Hz, 1H), 4.70 (d, J=5.49 Hz, 2H), 6.07 (s, 1H), 7.28 (d, J=8.24 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 12.13 (br s, 2H); MS (ESI) m/z 479.3 [M+H]+.