Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21]([NH2:22])[C:4]=2[N:3]=1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21]([NH:22][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]=2[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(NS(C)(=O)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-methyl-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazol-4-amine (186 mg), Et3N (0.15 mL) and DCM (20 mL) was added a solution of methanesulfonyl chloride (69 mg) in DCM at 0° C. and then the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with MeOH:DCM=1:30 to afford the desired product as a solid (180 mg, 80%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.40 (s, 3H), 2.98 (t, 4H, J=4.8 Hz), 3.21 (s, 3H), 3.68 (t, 4H, J=4.8 Hz), 5.96 (s, 2H), 6.37 (d, 1H, J=8.1 Hz), 6.80 (s, 2H), 7.35 (t, 1H, J=8.1 Hz), 7.60-7.71 (m, 2H), 7.85 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=8.1 Hz), 8.24 (d, 1H, J=8.1 Hz), 9.49 (br s, 1H); LC-MS: m/e=451 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](Cl)[C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1cc(Cl)c(C)nc1Oc1c(C)cc(C)cc1C
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC

Procedure:
A mixture of 4 chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester (500 mg, 1.56 mmol) and 1-ethyl-propyl-amine (0.8 ml) in 1 ml of DMSO was heated at reflux for 15 hours. The mixture was quenched with sat. ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give 445.6 mg of yellow solid. The solid was purified through silica gel column chromatography using 1:1 ratio of chloroform:hexane as eluent to give (289 mg, 50%)of the title compound as white crystals, mp 98-102° C.; 1H NMR (CDCl3) δ 8.04 (d, 1H), 6.85 (s, 2H), 6.06 (s, 1H), 3.85 (s, 3H), 3.32 (m, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 1.62 (m, 4H), 0.95 (t, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:10](=O)[NH:9]2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].[O-2].[Ca+2]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:10](=[S:28])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NC(c2ccc(Cl)cc2)c2ccccc2C1CCN1CCOCC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Ca+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: S=C1NC(c2ccc(Cl)cc2)c2ccccc2C1CCN1CCOCC1

Procedure:
20 millimoles of 1-(4-chlorophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one were introduced, while stirring, into a suspension of 8 millimoles of phosphorus pentasulfide and 32 millimoles of calcium oxide in 50 ml of toluene and the whole was heated for 7 hours under reflux until the reaction was completed. The reaction mixture was decanted off to remove the resinous residue and extracted twice with toluene. The combined organic solutions were concentrated and the product was recrystallized from isopropanol. M.p.: 228°-231°C (HCl)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([Cl:10])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)cc(Cl)c1O
Solvent: ClCCl
Product: Cc1cc(Br)cc(Cl)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 100 mL round bottom flask was added 4-bromo-2-chloro-6-methylphenol (1.00 g, 4.52 mmol), benzeneboronic acid (1.10 g, 9.04 mmol), cupric acetate (1.4 g, 7.70 mmol) and DCM (50 mL). TEA (4.0 mL, 29.0 mmol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:43]1([CH2:49][C:50]([N:52]=[C:53]=[S:54])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:25][N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:53]([NH:52][C:50](=[O:51])[CH2:49][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[S:54])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1)[CH3:24]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (105.6 mg) and (+)-10-camphorsulfonic acid (62 mg) in ethanol (2.5 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.5 ml) at room temperature, followed by stirring for 1 hour. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=1:1 to 4:1) to provide the titled compound (70.2 mg, 46%) as white powder.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:18][S@](C(C)(C)C)=O)[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1)(C(C)(C)C)(C)C.[ClH:25]>CO.O1CCOCC1>[ClH:25].[ClH:25].[NH2:18][C@@H:10]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1)[CH2:9][OH:8]
Reactant: Cc1ccnc([C@@H](CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccnc([C@H](N)CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106 %

Procedure:
(S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1.10 g, 2.97 mmol) was dissolved in MeOH (15 ml), and treated with 3.7 ml of a 4.0 M hydrogen chloride solution in dioxane. The reaction was stirred at ambient temperature for 2 hours, concentrated to dryness, and stored under high vacuum overnight to provide 0.71 g (106%) of crude (S)-2-amino-2-(4-methylpyridin-2-yl)ethanol dihydrochloride which was used directly in the next step.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:59]1[CH2:64][CH2:63][CH:62]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:61][CH2:60]1>CN(C=O)C.C(OCC)(=O)C>[N:1]1[N:2]=[C:3]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:59]3[CH2:60][CH2:61][CH:62]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:69])([CH3:71])[CH3:70])[CH2:63][CH2:64]3)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)c1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(-c3nnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoic acid (0.5 g, 1.4 mmol) in DMF (5 mL) was added HBTU (0.56 g, 1.4 mmol) follwed by triethylamine (0.392 mL, 2.8 mmol). The reaction mixture was stirred at room temperature for 15 minutes then tert-butyl piperidin-4-ylcarbamate (0.31 g, 1.5 mmol) was added and the mixture stirred at room temperature for an additional 3 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, gradient: 50% ethyl acetate in hexanes to 100% ethyl acetate). The tert-butyl (1-(4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoyl)piperidin-4-yl)carbamate was obtained as a white solid (0.478 g, 63%). M.p.=196-202° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.81 (br.s, 1H), 8.22 (dd, J=4.4, 1.6 Hz, 1H), 7.97 (dd, J=7.6, 1.6 Hz, 1H), 7.52-7.4 (m, 5H), 7.35 (d, J=8.0 Hz, 1H), 7.19 (dd, J=8.0, 1.2 Hz, 1H), 7.14 (dd, J=7.6, 1.2 Hz, 1H), 6.93 (dd, J=8.0, 1.6 Hz, 1H), 6.89 (br.s, 1H), 4.35-4.25 (m, 1H), 3.6-3.45 (m, 2H), 3.2-3.05 (m, 1H), 3.02-2.9 (m, 1H), 1.9-1.65 (m, 2H), 1.38 (s, 9H), 1.35-1.15 (m, 2H); LCMS [M+H]: 538.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:10]=[CH:11][C:3]=12
Reactant: Cc1nc(Cl)c2cn[nH]c2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Temperature: 90 °C
Yield: 98.9 %

Procedure:
A suspension of the above 4-chloro-6-methyl-1H-pyrazolo[3,4-d]pyrimidine (325 mg, 1928 μmol) in EtOAc (3 mL) was treated with 3,4-dihydro-2H-pyran (528 μL, 5783 μmol) and MP-TsOH resin (Biotage) (72 mg, 4.3 mmol/g, 0.15 eq) and the resulting suspension was heated at 90° C. for 3 h, after which time LCMS indicated essentially complete conversion. The solution was filtered, washed with EtOAc, and concentrated to give a pale yellow oil. Purification by flash chromatography (EtOAc/hexane; 5% to 20%) gave 4-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (482 mg, 98.9% yield) as a colorless oil. 1H NMR (400 MHz, d6-DMSO) δ 8.44 (s, 1H); 5.91-6.02 (m, 1H); 3.91-3.99 (m, 1H); 3.67-3.77 (m, 1H); 2.72 (s, 3H); 2.36-2.48 (m, 1H); 1.96-2.08 (m, 1H); 1.87-1.95 (m, 1H); 1.32-1.84 (m, 3H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[NH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])=[C:15]([O:31][CH3:32])[CH:14]=3)[C:5]=12.[CH2:39](I)[CH3:40].F[C:43](F)(F)[C:44]([OH:46])=[O:45]>CN(C)C=O>[C:44]([O-:46])(=[O:45])[CH3:43].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:33]3[CH2:34][CH2:35][NH2+:36][CH2:37][CH2:38]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:39][CH3:40])[C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])=[C:15]([O:31][CH3:32])[CH:14]=3)[C:5]=12
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2[nH]1
Reactant: CCI
Reactant: O=C(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)[O-]
Product: CCn1c(C(=O)Nc2ccc(-c3nn(C4CC[NH2+]CC4)c4ncnc(N)c34)cc2OC)cc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride, 60% suspension in mineral oil (0.006 g, 0.15 mmol) was added into the solution of N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1H-2-indolecarboxamide (0.08 g, 0.14 mmol) in N,N-dimethylforamide (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and at ambient temperature for 20 minutes. A solution of ethyl iodide (0.02 g, 0.14 mmol) in N,N-dimethylforamide (0.5 mL) was added in and the mixture was stirred at ambient temperature overnight. Ethyl iodide (0.01 g, 0.07 mmol) was added in and the mixture was stirred at ambient temperature overnight. Trifluoroacetic acid (3 mL) was added and the mixture was stirred at ambient temperature for 24 hours. The solvents and excess reagents were evaporated under reduced pressure and the residue was purified by preparative HPLC to yield 4-[4-amino-3-(4-{[(1-ethyl-1H-2-indolyl)carbonyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]hexahydropyridinium acetate (0.05 g, 0.09 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 8.27 (s, 1H), 8.14 (d, 1H), 7.71(d, 1H), 7.61 (d, 1H), 7.34 (s, 2H), 7.31 (t, 2H), 7.15 (t, 1H), 4.96 (m, 1H), 4.62 (q, 2H), 3.96 (s, 3H), 3.00 (m, 2H), 2.28 (m, 2H), 2.03 (m, 2H), 1.91 (s, 3H), 1.33 (t, 3H); MS: MH+ 511.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1>CC#N>[Br-:23].[Br:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:29][CH:30]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccc(Br)cc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccc(Br)cc3)(CC1)CC2
Product: [Br-]
Yield: 75.4 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0486 g, 0.165 mmol) and 4-bromophenyl 3-bromopropyl ether (0.0630 g, 0.214 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0731 g, 75.4%). EI-MS m/z 506 (M+) Rt (2.18 min).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:21][CH2:22][OH:23].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:31][O:30][C:27]1[N:26]=[CH:25][C:24]([C@H:20]([NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:22][OH:23])=[CH:29][CH:28]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: COc1ccc([C@H](N)CCO)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](CCO)Nc2ncnc3c2CN(c2ccc(C)cn2)CC3)cn1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (45 mg, 0.17 mmol) and (R)-3-amino-3-(6-methoxypyridin-3-yl)propan-1-ol (31 mg, 0.17 mmol) (prepared similarly according to the method for Intermediate 10) in acetonitrile (2 mL) and N,N-diisopropylethylamine (60 μL, 0.34 mmol) was subjected to microwave irradiation at 180° C. for 1 h. The reaction mixture was concentrated and purified by semi-prep HPLC to give a light yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9](=[O:15])[N:8]([OH:16])[C:7]1=[O:17].[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[C:28]([C:2]2[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][N:6]3[C:11]4[CH:12]=[CH:13][S:14][C:10]=4[C:9](=[O:15])[N:8]([OH:16])[C:7]3=[O:17])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: O=c1c2sccc2n(Cc2cccc(Br)c2)c(=O)n1O
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2cccc(Cn3c(=O)n(O)c(=O)c4sccc43)c2)c1

Procedure:
The title compound was prepared from 1-(3-Bromo-benzyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) and 3-acetyl-phenyl boronic acid via general procedure C. The crude product was purified by mass-triggered preparative HPLC.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=C.[H-].[Na+].Cl.ClCC[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>CN(C=O)C.O>[N:20]1([CH2:3][CH2:1][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:5]2=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCCCC1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCN1CCCCC1
Temperature: 45 °C
Yield: 46.7 %

Procedure:
A solution of 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (35 g, 0.2 moles) in DMF (250 ml) was added dropwise to a suspension of 80% sodium hydride (6 g, 0.2 moles) in DMF (50 ml). The reaction mixture was first heated at 45° C. for 30 minutes, allowed to cool at room temperature, and an additional amount of 80% sodium hydride (7.2 g, 0.24 moles) was added. Then 1-(2-chloroethyl)piperidine hydrochloride (44.16 g, 0.24 moles) was added portionwise and the reaction mixture was heated at 80° C.-90° C. for 3 hours. The mixture was then cooled at room temperature, adjusted to pH 3 with 37% aqueous HCl, and heated to 80° C. for additional 2 hours. The reaction mixture was poured into water and washed with ethyl acetate. The aqueous phase was adjusted to pH 8-9 with a saturated sodium carbonate solution and extracted into ethyl acetate. The organic layer was taken to dryness to give an ivory solid which after crystallization from isopropyl ether afforded 22.9 g of the title compound. M.p. 123° C.-125° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[NH:18][CH2:17][CH2:16][S:15]1)=[O:13].[CH:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([OH:43])=[O:42])=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[C:41]([C:40]1[CH:39]=[C:38]([CH:46]=[CH:45][CH:44]=1)[CH2:36][N:18]1[CH2:17][CH2:16][S:15][C@H:14]1[C:12]([O:11][C@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[CH2:9][C:8]1[C:7]([Cl:34])=[CH:6][N+:5]([O-:35])=[CH:4][C:3]=1[Cl:2])=[O:13])([OH:43])=[O:42]
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)c1cccc(CN2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (I5, 570 mg, 1.0 mmol) in DCM (5 mL) was added 3-formylbenzoic acid (180 mg, 1.2 mmol) followed by glacial AcOH (0.17 mL, 3.3 mmol). The reaction was stirred at room temperature for 18 h. Sodium triacetoxyborohydride (690 mg, 3.12 mmol) was added and the reaction was stirred at room temperature for 1.5 h. Additional 3-formylbenzoic acid (180 mg, 1.2 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. DCM (25 mL) and 1 N HCl (15 mL) were added to quench the reaction and the mixture was passed through a hydrophobic fit and the solvent was removed in vacuo to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C@H:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][CH2:10][NH:9]1.Cl[C:16]1[N:21]=[N:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][C:23]=2[OH:33])=[CH:18][CH:17]=1.FC(F)(F)C(O)=O>C1COCC1>[CH3:7][C@H:8]1[CH2:13][C@@H:12]([O:14][C:16]2[N:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][C:23]=3[OH:33])=[CH:18][CH:17]=2)[CH2:11][CH2:10][NH:9]1
Reactant: C[C@H]1C[C@@H](O)CCN1
Reactant: Oc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C[C@@H](Oc2ccc(-c3ccc(-n4cccn4)cc3O)nn2)CCN1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide (1.0 M in THF, 1.4 mL, 1.4 mmol) was added to cis-2-methylpiperidin-4-ol (0.10 g, 0.68 mmol) in THF (3 mL) and the mixture was stirred for 10 min at 50° C. 2-(6-Chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2 (0.08 g, 0.28 mmol) was added to the reaction at 0° C. and the mixture was stirred for 2 days at RT. Trifluoroacetic acid (0.3 mL) was added and the solvent was evaporated under reduced pressure. The crude material was purified via preparative HPLC (5 to 95% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). Enantiomer 1 and Enantiomer 2 were isolated via preparative SFC. Two solids (10 mg (10%) and (15 mg (16%)) were afforded.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=O.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:10].CC[O-].[Na+].Cl>O.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:9]([O:11][C:12]([C:13]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:2][N:3]2[CH2:7][CH2:6][CH2:5][C:4]=12)=[O:22])[CH3:10]
Reactant: NN1CCCC1=O
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)nn2c1CCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
To a solution of 1-amino-pyrrolidine-2-one hydrochloride (3.8 g, 27.8 mmol) (WO 02/094833) add ethylbenzoylacetate (4.3 mL, 25 mmol) followed by pyridine (10 mL) at room temperature under nitrogen. Stir the mixture at room temperature for 20 hours and then, dilute with water (50 mL) and extract with toluene (2×50 mL). Dry the combined organic layers (MgSO4) and concentrate in vacuo to give a brown oil, 6.23 g, 82% yield, and treat with NaOEt (freshly prepared, 3.1 g, 45.4 mmol, 2 equiv) in toluene at 120° C. for 8 hours. Cool the mixture to room temperature and add water (100 mL) and concentrated HCl until a pH of 4 is reached. Extract the mixture with EtOAc (3×200 mL) and dry (MgSO4) the combined organic layers and concentrate in vacuo. Purify the residue in a biotage system (eluent:CH2Cl2/MeOH 40:1) to obtain a yellow solid, 1.8 g, 36% yield. MS(ES+): m/z=257.1 (M+H)+