Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C.N(C(OCC)=O)=NC(OCC)=O>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Product: COc1ccc(OCCOc2nccnc2N2CCNCC2)c(Cl)c1

Procedure:
The title compound was prepared starting from 2-chloro-4-methoxyphenol (103 mg, 0.65 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (0.61 mmol; prepared in Example 52, Step 2) according to the procedure described in Example 52, Step 3, but utilizing diethyl azodicarboxylate (DEAD) instead of TMAD. Yield 50 mg (21%). HRMS m/z calcd for C17H21ClN4O3 (M)+ 364.1302, found 364.1307.
Reaction SMILES: [Cu][C:2]#[N:3].[C:4]([O:12][C@@H:13]1[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[O:15][C@H:14]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][C:35](I)=[N:36][C:37]=2[NH:41][CH2:42][CH:43]([C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:4]([O:12][C@@H:13]1[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@H:16]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[O:15][C@H:14]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][C:35]([C:2]#[N:3])=[N:36][C:37]=2[NH:41][CH2:42][CH:43]([C:44]1[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=1)[C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#C[Cu]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Copper(I) cyanide was added to a solution of (2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (440 mg, 0.494 mmol) (Preparation 67) in N′N′-dimethylformamide (10 ml). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was poured into water (15 ml). The precipitate was filtered off and stirred in dichloromethane (50 ml) for 10 minutes. The dichloromethane was filtered, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98: 2 by volume). The solvent was removed under reduced pressure to give the title compound (227 mg) as a foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH:32]([OH:33])[CH2:34][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(OCC2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)c1ccc(OCC(O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 28.4 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.15 g, 0.5 mmol) in acetonitrile (3.0 mL) was added 2-[(4-tert-butylphenoxy)methyl]oxirane (0.11 g, 0.55 mmol) followed by lithium perchlorate (0.058 g, 0.55 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The solvent was removed under vacuum. The crude product was purified by flash column chromatography (SiO2, 100% EtOAc to 2% methanol in EtOAc) to give the desired product as a purple solid (0.072 g, 29%). M.p.=137-140° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.35 (d, 2H), 6.9 (d, 2H), 4.15 (m, 1H), 4.0 (d, 2H), 2.95 (m, 3H), 2.8 (m, 2H), 2.65 (m, 2H), 2.55 (t, 2H), 2.15 (d, 2H), 1.9 (m, 2H), 1.3 (s, 9H); LCMS: 508 [M+H].
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:15])=[C:7]([CH3:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]=[S:3].[NH3:16]>ClCCl>[CH3:14][C:7]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([NH:1][C:2]([NH2:16])=[S:3])[S:5][C:6]=1[CH3:15]
Reactant: N
Reactant: CCOC(=O)c1c(N=C=S)sc(C)c1C
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(N)=S)sc(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
To a solution of ethyl 2-isothiocyanato-4,5-dimethylthiophene-3-carboxylate (Example 50b) (1.21 g, 5.27 mmol) in dichloromethane (10 mL) was added ammonia (7 M in MeOH, 1.12 mL, 7.91 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 3 h, quenched with water and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The dark orange residue was purified by chromatography on silica gel (Gradient 0-50% EtOAc in Hexanes) to give the title compound (37.1 mg, 3%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H, J=7.1 Hz), 2.18 (s, 3H), 2.19 (s, 3H), 4.30 (q, 2H, J=7.1 Hz), 8.43 (s, 2H), 11.38 (s, 1H). MS 259 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: CN1CCNCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(C)CC1
Yield: 21.8 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and N-methyl piperazine (0.126 mL, 1.14 mmol) were reacted as described in Example 57B to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea as a colorless solid (49 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.00 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.26-7.49 (m, 5H), 6.49 (s, 1H), 4.25-4.29 (m, 2H), 3.98 (s, 3H), 2.75-2.79 (m, 2H), 2.20-2.60 (m, 8H), 2.15 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 592 (M+H)+.
Reaction SMILES: [BH4-].[Na+].Cl[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:5]([F:8])([F:7])[F:6]>C1COCC1>[F:6][C:5]([F:7])([F:8])[CH2:4][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Oc1ccccc1C(Cl)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccccc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium Borohydride (0.930 g) was added to a solution of 2-(1-chloro-2,2,2-trifluoroethyl)phenol (2.6 g) in THF (30 ml). The reaction mixture was then stirred for 14 hrs at room temperature under an atmosphere of nitrogen, after which time the reaction was quenched with 1N HCl (50 ml) and partitioned between 1N HCl (100) and ethyl acetate (200 ml), the organics were separated and dried over magnesium sulfate, filtered and solvent evaporated in vacuuo to afford title compound as a semi solid (2.4 g). 1H NMR (CDCl3): δ 3.50 (q, J=21.06 Hz 2H), 6.80 (m, 1H), 7.00 (m, 1H), 7.25 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:9]2[CH2:11][CH2:10]2)[CH:3]=1.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]1[CH2:11][CH2:10]1)=[N+:16]=[N-:17]
Reactant: Nc1ccc(Cl)cc1C1CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-chloro-2-cyclopropylaniline (182 mg, 1.086 mmol) in acetic acid (15 ml) and water (15 ml) was stirred and cooled to 0° C. A solution of sodium nitrite (74.9 mg, 1.086 mmol) in water (1.4 ml) was added dropwise and the mixture was stirred under ice cooling for 10 mins. A solution of sodium azide (70.6 mg, 1.086 mmol) in water (1.5 ml) was added dropwise and was stirred under ice cooling for 1 hr and then at RT 30 mins. To the product mixture was added 2M NaOH (aq) until basic and this was extracted with EtOAc. The organic extract was washed with sat. NaHCO3(aq) and dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a dark yellow/brown oil. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:42])[O:33][C@@H:34]1[C@H:41]2[C@H:37]([O:38][CH2:39][CH2:40]2)[O:36][CH2:35]1)[C@H:9]([OH:30])[CH2:10][N:11]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([S:12]([N:11]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10][C@@H:9]([OH:30])[C@@H:8]([NH:31][C:32](=[O:42])[O:33][C@@H:34]2[C@H:41]3[C@H:37]([O:38][CH2:39][CH2:40]3)[O:36][CH2:35]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1cccc(N)c1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
A solution of (3R,3aS, 6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (239 mg, 0.394 mmol) in absolute ethanol (3 mL) was combined with Palladium on carbon (10 wt %, 25 mg) and reduced under a Hydrogen atmosphere over 16 hours. The reaction was filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 3:2 ethyl acetate : hexane. Fractions containing the product were combined and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(3-aminophenyl)sulfonyl](1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate (153 mg, 67%) as a white solid. H1-NMR (chloroform-D3): 0.96 (m, 6H), 1.62 (m, 7H), 3.05 (m, 5H), 3.76 (m, 2H), 3.96 (m, 6H), 4.19 (m, 1H), 4.88 (m, 1H), 5.07 (m, 1H), 5.69 (d, 1H), 6.95 (d, 1H), 7.14 (s, 1H), 7.28 (m, 7H). MS(ESI): 600(M+Na).
Reaction SMILES: C([O:8][C@@H:9]([C:11]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:14]2=[N:13][N:12]=1)[CH3:10])C1C=CC=CC=1.CC#N.[Si](I)(C)(C)C>CCOC(C)=O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:14]3[N:15]([C:11]([C@H:9]([OH:8])[CH3:10])=[N:12][N:13]=3)[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@@H](C)OCc3ccccc3)n21
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@@H](C)O)n21
Temperature: 60 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
To a round bottom flask was added (R)-4-(3-(1-(benzyloxy)ethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (40 mg, 0.061 mmol), CH3CN (2 ml) and TMSI (244 mg, 1.22 mmol). The reaction was stirred at 60° C. under argon for 20 hr. After this time, the solution was cooled to rt and diluted with EtOAc (50 ml). The resulting organic solution was extracted with water (20 ml), 10% NaHSO3 (20 ml) and saturated NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (8 g silica gel) eluting with a gradient of 20% to 80% EtOAc/Hex to give the product (R)-4-(8-(4-chlorophenyl)-3-(1-hydroxyethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (15 mg, 44% yield).
Reaction SMILES: [C:1]([C:3]([NH2:8])([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].[CH2:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[F:22])[C:10]#[CH:11]>>[C:1]([C:3]([NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([O:12][CH2:9][C:10]#[CH:11])=[C:14]([F:22])[CH:15]=1)([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2]
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Reactant: CC(C)C(C)(N)C#N
Product: C#CCOc1ccc(C(=O)NC(C)(C#N)C(C)C)cc1F

Procedure:
According to the same method as that of Production Example 1, 1-cyano-1,2-dimethylpropylamine was used in place of 2,2-dimethylpropylamine, and 4-(2-propynyloxy)-3-fluorobenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1-cyano-1,2-dimethylpropyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 27 of the present invention) represented by the formula:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][CH:19]=[C:20]([C:22](O)=[O:23])[CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:58]1[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([N:58]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]3)=[O:23])[CH:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1csc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: C1CCCNCC1
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: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid benzyl ester (0.095 g, 0.27 mmol) was dissolved in DMF (2 mL). DIPEA (0.54 mmol), HATU (0.27 mmol) and homopiperidine (0.27 mmol) were added and the reaction stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic solution was separated and dried with magnesium sulphate, filtered and the solvent removed under vacuum. The residue was purified by HPLC, eluting with 40%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.032 g). LCMS m/z 427.29 [M+H]+ RT=12.22 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.4-7.35 (m, 4H), 7.35-7.3 (m, 1H), 7.25 (s, 1H), 6.9 (s, 1H), 5.15 (s, 2H), 4.3 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H), 3.00-2.90 (m, 3H), 2.0 (m, 2H), 1.8 (m, 2H), 1.75-1.5 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=O)[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]([CH3:33])([CH3:32])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]([CH3:33])([CH3:32])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(c2ccc(OCc3ccccc3)cc2)CCC1NC(=O)CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(C)CN(c2ccc(OCc3ccccc3)cc2)CCC1NCCCc1ccccc1

Procedure:
Following the procedure of example 40b, (RS)-N-[1-(4-benzyloxy-phenyl)-3,3-dimethyl-piperidin-4-yl]-3-phenyl-propionamide (450 mg) was reduced with LiAlH4 to give (RS)-[1-(4-benzyloxy-phenyl)-3,3-dimethyl-piperidin-4-yl]-(3-phenyl-propyl)-amine as a white solid (260 mg; 60%, MS: m/e=429.4 (M+H+)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:17]1([NH:20][CH3:21])[CH2:19][CH2:18]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[N:20]([CH:17]1[CH2:19][CH2:18]1)[CH3:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CNC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1 eq.), cyclopropyl-methyl-amine hydrochloride (1.2 eq.), HOBt (1.5 eq.), EDAC (1.5 eq.) and TEA (3 eq.) in DMF was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was washed with brine, dried, concentrated, purified on a silica gel column to give (S)-2-(cyclopropyl-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH:10]=O)=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][CH:8]=2)[CH:7]=1
Reactant: O=CNCc1ccc(F)cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc2cncn2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
In a round-bottomed flask, N-(5-fluoro-pyridin-2-ylmethyl)-formamide (612 mg, 3.97 mmol) was dissolved in toluene (16 ml) and phosphorus oxychloride (0.68 ml, 7.3 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath for 4 h then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 517 mg (96%) of 6-fluoro-imidazo[1,5-a]pyridine as a light brown oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.16 (s, 1H), 7.84-7.94 (m, 1H), 7.50 (s, 1H), 7.46 (dd, J=9.8, 5.3 Hz, 1H), 6.69 (ddd, J=9.8, 7.7, 2.1 Hz, 1H).
Reaction SMILES: [N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=[C:16]([NH2:25])[C:15]=3[N:14]=[C:13]2[CH2:26][CH2:27][CH3:28])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>[Pt](=O)=O>[N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[N:17]=[C:16]([NH2:25])[C:15]=3[N:14]=[C:13]2[CH2:26][CH2:27][CH3:28])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(N)nc3c(c2n1CCCCC(=O)N1CCOCC1)CCCC3
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 1-(5-morpholin-4-yl-5-oxopentyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (1.66 g, 4.19 mmol, prepared in Example 34), platinum (IV) oxide (1.5 g, 6.6 mmol), and trifluoroacetic acid (25 mL) was placed in a Parr vessel and shaken under hydrogen pressure (40 psi, 2.8×105 Pa) overnight. The reaction mixture was filtered through a layer of CELITE filter agent, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol). The resulting solid was triturated three times with 10% aqueous sodium hydroxide, isolated by filtration, and washed with water to provide 0.468 g of 1-(5-morpholin-4-yl-5-oxopentyl)-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 158-160° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:18]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)O)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: Cn1ccnc1C(O)c1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Solvent: ClCCl
Product: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Temperature: 40 °C
Yield: 53 %

Procedure:
A Teflon-capped high-pressure glass bottle was charged with (6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)(1-methyl-1H-imidazol-2-yl)methanol (2.2 g, 6.4 mmoles, 1.0 eq.), dry CH2Cl2 (60 ml) and solid P2I4 (7.3 g, 12.9 mmoles, 2.0 eq.). The bottle was flushed with N2 and heated at 40° C. for 60 hours. The reaction was quenched with NaHCO3 (200 ml, 1.0 M in water), extracted (3×200 ml CH2Cl2), the organic layer was dried with MgSO4 and concentrated on rotary evaporator. The crude residue was purified by flash chromatography (30%→70% gradient of 10% MeOH/90% EtOAc in hexanes on a 330 g silica gel column). The purified product was crystallized from hot EtOAc. Yield: 1.1 g (53%). Repeated crystallization provided additional 0.7 g (34%) having equal purity. (0.19 g, 53% yield). M/e+ 325 for C18H15F2N4 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.35 (d, J=1.8 Hz, 1H), 7.68 (dd, J=7.7, 5.5 Hz, 2H), 7.57 (dd, J=9.9, 5.1 Hz, 1H), 7.25 (d, J=1.1 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 6.92 (s, 1H), 6.74 (s, 1H), 4.50 (s, 2H), 3.19 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29]CC3C=CC=CC=3)=[O:28])[CH2:22]2)=[CH:8][S:9][C:10]=1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:5])[CH3:2].[OH-].[Na+]>CCO>[CH2:12]([CH:22]1[CH:21]([C:7]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[S:9][CH:8]=2)[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([OH:29])=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)csc1NC(=O)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(C2CCCN(C(=O)O)C2Cc2ccccc2)csc1NC(=O)c1cccc(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 56 (96 mg, 0.19 mmol) in EtOH (5 ml) at room was added 1.0 N NaOH (aq.) (0.4 ml). The mixture was stirred at 60° C. for 2 hrs. The solvent was removed under vacuum. The residue was suspended in 1.0 N HCl (aq.) (2 ml) and extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum to give the crude product which was purified using preparative HPLC to give 57 (40.2 mg). 1H NMR (DMSO-d6) δ 1.44 (m, 1H), 1.51 (m, 1H), 1.73 (m, 1H), 2.01 (m, 1H), 2.88 (m, 2H), 4.03 (m, 1H), 4.21 (m, 1H), 5.10 (m, 2H), 6.87 (s, 1H), 7.36 (m, 5H), 7.54 (m, 1H), 7.68 (m, 2H), 7.75 (m, 1H), 12.58 (b, 1H), 13.74 (b, 1H) ppm.