Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[CH2:13]([NH:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[CH:23][C:22]=1[NH2:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH2:13]([NH:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:24]=[CH:23][C:22]=1[NH:33][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: Nc1cnc(N2CCOCC2)cc1NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cnc(N3CCOCC3)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Propylphosphonic acid anhydride, cyclic trimer (0.356 ml; 0.610 mmol) is added to a mixture of 1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (85.000 mg; 0.508 mmol), N4-Benzyl-6-morpholin-4-yl-pyridine-3,4-diamine E-2.3 (133.000 mg; 0.468 mmol) and triethylamine (0.176 ml; 1.271 mmol) in THF (3.000 ml). The reaction mixture is stirred overnight (16 h) at RT. The reaction is quenched with 1M NaOH (2 ml) and diluted with water, then extracted twice with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated in vacuum. The residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 12 g; gradient: DCM/MeOH=100%/0% to 90%/10%; flow rate=30 ml/min; 28 column volumes; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduce pressure.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[NH:41][C:40]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[CH:39][C:38]2=[O:49]>O1CCOCC1.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>[N:43]1([C:40]2[NH:41][C:42]3[C:37]([C:38](=[O:49])[CH:39]=2)=[CH:36][CH:35]=[CH:34][C:33]=3[C:7]2[C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[C:12]=3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1
Reactant: O=c1cc(N2CCOCC2)[nH]c2c(Br)cccc12
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c3c2oc2ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1cc(N2CCOCC2)[nH]c2c(-c3ccc([N+](=O)[O-])c4c3oc3ccccc34)cccc12
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
In a Schlenk tube, 1-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) dibenzofuran (12) (500 mg, 1.47 mmol) and potassium carbonate (480 mg, 3.69 mmol) were solubilised in dioxane (10 mL) and degassed. Concurrently, 8-bromo-2-morpholin-4-yl-1H-quinolin-4-one (21) (380 mg, 1.23 mmol) and Pd(PPh3)4 (71 mg, 0.06 mmol) were solubilised in dioxane (10 mL) and degassed. The solutions were mixed together in a microwave vessel, which was placed into the microwave reactor at 180° C. for 30 min. Upon cooling, DCM (20 mL) was added. The solution was washed with water (20 mL), then dried on magnesium sulfate and evaporated. The residue was purified by flash chromatography using AcOEt/EP (8:2) as eluant to furnish the title compound (303 mg, 0.74 mmol, 60%) as a yellow solid: Rf=0.67 (AcOEt); mp: 247° C.; λmax (EtOH)/nm 251; IR (cm−1) 3421, 2852, 2360, 2333, 1614, 1573, 1500, 1435, 1429, 1348, 1309, 1233, 1199, 1152, 1124, 1039, 991, 917, 866, 823; 1H NMR, (300 MHz, CDCl3) δ 3.04 (4H, m, 2×CH2—N-morpholine), 3.54 (4H, m, 2×CH2—O-morpholine), 5.92 (1H, s, H-3), 7.19-7.45 (2H, m), 7.51-7.58 (2H, m), 7.65-7.70 (2H, m), 8.31 (2H, m), 8.67 (1H, d, J=7 Hz); MS (EI) m/z 442.29 M+; HRMS calcd for C25H20N3O5 [M+H]+ 442.1397, found 442.1398.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[CH3:14][S:15]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=3)[S:24][C:23]=2[CH:38]=1)(=[O:17])=[O:16].ClCCl.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl>[CH3:14][S:15]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([C:9](=[O:11])[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][Br:1])=[CH:13][CH:12]=3)=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=3)[S:24][C:23]=2[CH:38]=1)(=[O:16])=[O:17]
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Reactant: O=C(O)c1ccc(OCCBr)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCBr)cc2)cc1
Temperature: 0 °C

Procedure:
One g. of 4-(2-bromoethoxy)benzoic acid was converted to the acid chloride, and was combined with 1.2 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene, 20 ml. of dichloromethane and 0.5 ml. of trifluoromethanesulfonic acid. The mixture was stirred under reflux overnight, and was then poured into ice-water. The organic layer was separated, washed with sodium carbonate solution, dried and evaporated under vacuum to obtain 2.1 g. of brown oil. The oil was chromatographed over a 4×8 cm. silica gel column with 9/1 toluene/ethyl acetate and the product-containing fractions were combined and evaporated under vacuum to obtain 1.8 g. of purified product as an oil. The product was identified by its MH+ molecular ion, m/e 626, in the field desorption mass spectrum and by an absorption maximum in the infrared spectrum, in chloroform, at 1645 cm.-1 attributable to the CO function. A small sample was recrystallized from methanol to obtain white crystals, m.p. 105°-107°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH:52]=1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:61]6[CH2:62][CH2:63][N:58]([CH2:57][C:53]7[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=7)[CH2:59][CH2:60]6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: c1cncc(CN2CCNCC2)c1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(Cc5cccnc5)CC4)cc3F)cn2)cc1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (54 mg) and 1-pyridin-3-ylmethyl-piperazine (22 mg) obtained in Step A in Example 1-D-315 instead of 3-(aminomethyl)pyridine used in Step B in Example 1-D-19, treatment was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-phenyl]-(4-pyridin-3-ylmethyl-piperazin-1-yl)-methanone, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-315) as a yellow powder (32.0 mg, 83%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:10]=1)C1C=CC=CC=1.[H][H]>[Ni].C(O)C>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][O:16][CH2:15][C:11]1[N:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCOCc1cccc(OCc2ccccc2)n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: C[Si](C)(C)CCOCOCc1cccc(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
7 g of Raney Nickel are added to a solution of 7 g of 2-benzyloxy-6-(2-trimethylsilanyl-ethoxymethoxy-methyl)pyridine in 75 ml of ethanol saturated with hydrogen. The suspension is stirred vigorously under a low hydrogen pressure at room temperature for 1 hour 30 minutes. The solid in suspension is removed by filtration on celite and then the ethanol is evaporated off. The title product is isolated by chromatography on a silica column (eluent: dichloromethane/methanol; 98:2). 4 g of a colorless oil are recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:30]([C:32]1[CH:33]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[F:38])#[N:31]>C1COCC1>[C:30]([C:32]1[CH:33]=[C:34]([S:39]([N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=2)(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[F:38])#[N:31]
Reactant: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: 0 °C
Yield: 63 %

Procedure:
To a −40° C. solution of N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 20, 2.32 g, 8.84 mmol) in THF (60 ml) was added LiHMDS (9.72 ml, 9.72 mmol, 1M in THF) keeping the temperature below −35° C. The reaction mixture was warmed to 0° C. for 40 minutes before re-cooling to −40° C. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.94 g, 8.84 mmol) was added to the reaction mixture as a solution in THF (10 mL) and the reaction mixture allowed to warm to room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with saturated brine (100 mL), dried over MgSO4, filtered and the solvent removed under vacuum. The crude material was purified by silica gel column chromatography eluting with 20-40 EtOAc in heptane followed by reverse phase chromatography eluting with 0-100% MeCN in H2O to afford the title compound as a brown gum (2.48 g, 63%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2cccn2)nc1
Solvent: ClCCl
Product: ClCc1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of alcohol (III) (10.5 g, 59.9 mmol) in CH2Cl2 (150 ml), SOCl2 (36 g, 22 ml, 299.6 mmol) was added and the resulting reaction mixture was stirred at room temperature for a period of between 12 to 18 hours. The excess SOCl2 was quenched with saturated aqueous NaHCO3. The resulting mixture was extracted with CH2Cl2 and washed with brine. Removal of solvent gave a compound of formulae (11.15 g, 95% yield) as a white solid. MS-ESI=194.06, 196.06, 1H NMR (ppm): 8.59 (H3′, d), 8.43 (H6, d), 8.03 (H2, d), 7.89 (H3, dd), 7.78 (H5′, s), 6.50 (H4′, t), 4.65 (—CH2-).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>COC(O)C.[Pt](=O)=O>[N:1]1[CH:2]=[N:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: c1cn2ncnc2cn1
Agent: O=[Pt]=O
Agent: COC(C)O
Product: c1nc2n(n1)CCNC2
Reaction time: 21.5 h

Procedure:
Platinum(IV) oxide (2.75 g, 12.1 mmole) was added to a suspension, saturated with nitrogen, of CaO (9.30 g, 166 mmole) and [1,2,4]-triazolo[1,5-a]pyrazine (18.1 g, 151 mmole) in methoxyethanol (150 ml). The reaction mixture was stirred for 21.5 hours under a hydrogen atmosphere. The catalyst was filtered off through filter earth and washed with DCM/ethanol (9:1). The filtrate was concentrated, and the solvent was removed firstly with toluene and then with 2-propanol. The residue was taken up in ethyl acetate, filtered again through filter earth, washed with ethyl acetate, and concentrated. The residue was washed with hot 2-propanol and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][C:5]([F:8])=[CH:4][CH2:3]1.[H][H]>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][CH:5]([F:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: COC(=O)C1(N)CC=C(F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1(N)CCC(F)CC1

Procedure:
Methyl 1-amino-4-fluoro-3-cyclohexenecarboxylate (52 mg) was dissolved in the mixed solvents of methanol (2 mL) and ethyl acetate (2 mL), and 10% palladium-carbon (35 mg) was added and hydrogen gas was introduced for 14 hours. The insoluble matter was filtered and the solvent was removed by distillation under reduced pressure, and a mixture of the desired matter (BB09, 38 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)[CH:23]=[CH:24][CH:25]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:32])[F:33])[CH:21]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: OCCCC#Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2cccc(C(F)(F)F)c2)cc1C

Procedure:
In analogy to the procedure described for example 21A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-(3-trifluoromethyl-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:7])=[CH:4][N:3]=1.[N:28]1([CH2:34][CH2:35][OH:36])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:36][CH2:35][CH2:34][N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:30][CH2:29]1
Reactant: OCCN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(Cl)nc1
Product: NC(=O)c1ccc(N2CCN(CCO)CC2)nc1

Procedure:
6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.143 mmol) was used in general procedure 3 with 2-(piperazin-1-yl)ethanol (0.71 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(4-(2-hydroxyethyl)piperazin-1-yl)-nicotinamide. MS (Q1) 498.0 (M)+
Reaction SMILES: [BrH:1].[CH2:2]([NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrBr.O>C(O)=O>[CH2:2]([NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:1])[CH:17]=2)[O:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Br
Reactant: c1ccc(CNC[C@H]2CCc3ccccc3O2)cc1
Agent: BrBr
Solvent: O=CO
Solvent: O
Product: Brc1ccc2c(c1)CC[C@H](CNCc1ccccc1)O2
Temperature: 16 °C
Reaction time: 1.17 h
Yield: 84.3 %

Procedure:
In a 30 L reaction vessel, N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine hydrobromide (2173 g, 6.5 moles, 1.0 eq.) was suspended in 11.4 L formic acid. The suspension was cooled to 16° C., then bromine (1071 g, 6.7 moles, 1.03 eq.) was added over a 60 minutes, maintaining the reaction temperature between 15 and 16° C. After 70 minutes, a HPLC probe indicated the reaction to be complete. To the reaction mixture was then added 15.6 L water (temperature increased to 21° C.). The light reaction mixture was then stirred for 30 minutes at room temperature, then the product was filtered and washed with 3.9 L water. The 3.14 kg of light gray moist product was then suspended in 9.75 L dichloromethane. To this suspension was added 13 L 1M NaHCO3. Foaming ensued and the suspension became a bi-phasic solution. The aqueous phase was separated (14.5 L; pH=8) and the organic phase was washed with 6.5 L water. The phases were separated and the organic phase evaporated at 45° C. to yield 1820 g of N-benzyl-N-{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amine.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=O)[CH:14]2[C:17]([CH3:19])([CH3:18])[CH:10]([C:11](=O)[NH:12][C:13]2=O)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:8]1[CH2:9][CH:10]2[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:13][NH:12][CH2:11]2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C2C(=O)NC(=O)C1C(=O)N(Cc1ccccc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C2CNCC1CN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A solution of 3-benzyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraone (980 mg; 3.26 mmol; from step (c) above) in 1,4-dioxane (25 mL) was added dropwise to a suspension of lithium aluminium hydride (990 mg; 26.1 mmol) in 1,4-dioxane (30 mL) at 0° C. The mixture was refluxed overnight, cooled to 0° C. whereafter water (1.0 mL), 15% aqueous sodium hydroxide (1.0 mL), and more water (3.0 mL), were added sequentially. After stirring for 1 h at 0° C., the mixture was filtered through a small pad of Celite, washing the Celite cake with ethyl acetate (100 mL). The filtrate was evaporated to give the sub-title compound (676 mg; 85% crude yield) as a colourless oil which was used directly in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:30][S:31]([CH:34]=[CH2:35])(=[O:33])=[O:32]>CC(N(C)C)=O>[CH:27]([O:26][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[C:9]4[CH2:10][CH2:11][CH2:12][C@@H:3]([NH:2][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])[C:4]=4[CH:5]=[CH:6][CH:7]=3)[N:17]=2)=[CH:25][C:22]=1[C:23]#[N:24])([CH3:29])[CH3:28]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NCCS(C)(=O)=O)no2)cc1C#N
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 3 (20 mg, 0.05 mmol) in DMA (0.5 mL) was added TEA (136 μL, 0.97 mmol) and methylvinylsulfone (52 mg, 0.5 mmol). The reaction was heated to 80° C. for 24 h. The crude reaction mixture was purified by preparative HPLC to give (R)-2-isopropoxy-5-(3-(5-((2-(methylsulfonyl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 48. LCMS-ESI (m/z) calculated for C25H28N4O4S: 480.6; found 481.2 [M+H]+, tR=2.58 min. 1H NMR (400 MHz, CDCl3) δ 8.37 (t, J=9.1 Hz, 1H), 8.31 (dd, J=8.9, 2.2 Hz, 1H), 8.08 (d, J=7.1 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 4.85-4.73 (m, 1H), 4.53 (t, J=5.0 Hz, 1H), 3.63 (dd, J=15.3, 4.0 Hz, 2H), 3.61-3.50 (m, 2H), 3.33-3.17 (m, 1H), 3.18-3.04 (m, 1H), 3.04 (d, J=8.6 Hz, 3H), 2.16 (ddd, J=29.6, 18.8, 12.2 Hz, 2H), 2.00 (dd, J=36.4, 18.4 Hz, 2H), 1.47 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23](Br)[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:27]1([CH2:33][C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C([O-])(=O)C.[K+].C(#N)C.C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([C:37]4[CH:36]=[CH:35][C:34]([CH2:33][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:39][CH:38]=4)[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ncc2c(c1O)c1cc(-c3ccc(CN4CCCCC4)cc3)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 140 °C
Yield: 32.7 %

Procedure:
A mixture of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (150 mg, 0.35 mmol), 4-piperidin-1-ylmethylphenyl boronic acid (126 mg, 0.6 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (27 mg, 0.04 mmol) in 2N aqueous potassium acetate (1.1 mL) and acetonitrile (1.4 mL) was heated under microwave irradiation at 140° C., for 30 minutes. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL) resulting in the formation of a precipitate. The supernatant liquors were decanted and the precipitate was dissolved in 10% methanol in DCM. The decanted liquors were partitioned and the aqueous phase was washed with 10% methanol in DCM (2×10 mL). The combined organic phases were concentrated in vacuo and the resultant residue purified by column chromatography (silica, 2 g cartridge, Si-SPE, 0-20% MeOH in DCM) afforded the crude product which was triturated with acetonitrile (1 mL) and methanol (1 mL) to afford the title compound as a beige solid (60 mg, 31%). LCMS (Method B): RT=2.65 min, M+H+=524.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][N:31](C(OC(C)(C)C)=O)[CH:30]([C:40]([O:42][C:43](C)(C)C)=[O:41])[CH2:29][CH2:28]2)[CH:9]=1.Cl>CO.O1CCOCC1>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][NH:31][CH:30]([C:40]([O:42][CH3:43])=[O:41])[CH2:29][CH2:28]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CN1
Temperature: 80 °C

Procedure:
Di-tert-butyl 5-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1,2-dicarboxylate (370 mg, 0.46 mmol) in methanol (12.6 mL) was treated with 4N hydrogen chloride in dioxane (5.4 ml). The reaction mixture was heated at 80° C. for 16 h, cooled to room temperature and concentrated in vacuo. The residue was purified by prep-LC to afford the title compound: LC/MS RT=2.31 min. Mass calculated for, M+H 403.18, observed 403.18.