Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: COCCN
Product: COCCNc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and 2-methoxyethylamine (0.26 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(2-methoxy-ethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (65 mg, 65%) as an off-white powder. ES-HRMS m/e calcd for C18H29N4O2 (M+H+) 333.2285, found 333.2282.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:20]1[N:34]=[C:33]([F:35])[CH:32]=[CH:31][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[O:23].CCCCCC.CC(=O)OCC>CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[N:34]=[C:33]([F:35])[CH:32]=[CH:31][C:21]=2[C:22]([NH:24][CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[O:23])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NCc1cccs1)c1ccc(F)nc1F
Reactant: O=S(=O)(CCS)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(NCc1cccs1)c1ccc(F)nc1SCCS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
258 mg (2.3 mmol) of potassium tert-butoxide were added at 0° C. to a solution of 465 mg (2.3 mmol) of 2-(phenylsulfonyl)ethanethiol in DMF (7 ml). After stirring for 10 min at 0° C., 381 mg (1.5 mmol) of 2,6-difluoro-N-(thiophen-2-ylmethyl)nicotinamide were added and the mixture was then heated for 16 hours at 50° C. Dilution with EA and washing with brine were then carried out. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 298 mg (0.68 mmol, 45%) of 2-[2-(benzenesulfonyl)ethylthio]-6-fluoro-N-(2-thienylmethyl)-nicotinamide. MS: m/z 437.0 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10]2)[CH2:6]1)=[O:4].[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:20]=3)=[C:10]2[Br:33])[CH2:8]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](n2c(Br)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
The title compound is prepared in analogy to Example 103 starting from 12.9 g (30.11 mmol) cis-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester (see Step 3.1 above) and 6.07 g (33.12 mmol) N-bromosuccinimide in 250 ml dry N,N-dimethylformamide. After work-up, the raw material is purified by chromatography on silicagel (solvent: hexane-ethyl acetate 1:1). Analytical HPLC: tR=11.85 min (Grad 1); ES-MS: m/eo=506.9 and 509.9; NMR (DMSO-d6): 8.14/s (1H), 7.3-7.5/several m's (6H), 7.09/“d” (1H); 7.05/s (1H); 6.98/“d” (1H); 5.5-6.5/b (NH2); 5.13/s (2H); 5.11/m (1H); 3.66/s (3H); 3.35-3.5/m (2H); 3.08/m (1H); 2.58-2.7/m (2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3OC)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3OC)c2)=C(C)C1=O
Yield: 81.7 %

Procedure:
N-(2-Methoxypyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.150 g, 0.312 mmol) was dissolved in methanol (5 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=3:1) to obtain the titled compound (0.112 g, 0.255 mmol, 82%).
Reaction SMILES: [CH3:1][N:2]([C:14]([C:16]1[CH:21]=[C:20]([O:22]CC2C=CC=CC=2)[C:19]([O:30]CC2C=CC=CC=2)=[C:18]([CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:17]=1)=[O:15])[NH:3]C(OCC1C=CC=CC=1)=O>CN(C)C=O>[CH3:1][N:2]([C:14]([C:16]1[NH:17][C:18]([CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:19]([OH:30])[C:20](=[O:22])[CH:21]=1)=[O:15])[NH2:3]
Reactant: CN(NC(=O)OCc1ccccc1)C(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(CNC(=O)OC(C)(C)C)n1
Solvent: CN(C)C=O
Product: CN(N)C(=O)c1cc(=O)c(O)c(CNC(=O)OC(C)(C)C)[nH]1
Yield: 82.4 %

Procedure:
To a solution of the compound of Example 36d (1.49 g, 2.37 mmol) in 30 ml dimethylformamide 0.7 g 10% palladium on carbon catalyst were added and a stream of hydrogen was bubbled through the mixture for 1 hour. The catalyst was filtered off and the filtrate evaporated in vacuo. Trituration of the residue with ether yielded 0.61 g of the desired product. M.P. 188°-190° C. (dec.)
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]2([CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]2([CH2:55][CH2:54][N:53]([C:32]([N:12]3[C@@:13]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([CH3:24])[C@@:14]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)([CH3:16])[N:15]=[C:11]3[C:8]3[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=3[O:35][CH2:36][CH3:37])=[O:33])[CH2:52][CH2:51]2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (Syntech Labs) to give the title compound. HR-MS (ES, m/z) calculated for C43H56Cl2N5O4 [(M+H)+] 776.3704, observed 776.3699.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[N:1]1([C@@H:6]2[CH2:7][CH2:8][C@H:9]([NH2:12])[CH2:10][CH2:11]2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:22]([OH:24])([C:21]([F:26])([F:25])[F:20])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2cncn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](n2cncn2)CC1

Procedure:
Sodium hydride (60%, 0.034 g, 0.86 mmol) was added portionwise to a solution of 1H-1,2,4-triazole (0.064 g, 0.92 mmol) in N,N-dimethylformamide (2 mL). After stirred for 5 min, trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl methanesulfonate (0.18 g, 0.61 mmol) was added. The resulting mixture was stirred at 65° C. over weekend. The cooled mixture was poured into ice-cold water, extracted with EtOAc. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in EtOAc) to give tert-butyl [cis-4-(1H-1,2,4-triazol-1-yl)cyclohexyl]carbamate (0.14 g, 86%). LCMS calculated for C13H23N4O2 (M+H)+: m/z=267.2. Found: 267.1. This carbamate intermediate was treated with trifluoroacetic acid (0.28 mL, 3.7 mmol) in methylene chloride (1 mL) at room temperature for 1 h and then concentrated to give the desired product as TFA salt. LCMS calculated for C8H15N4 (M+H)+: m/z=167.1. Found: 167.2.
Reaction SMILES: [CH3:1][C@@H:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[CH3:33]/[C:34](=[CH:40]\[C@@H:41]([N:45]([CH3:54])[C:46](=[O:53])[C@H:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[NH2:48])[CH:42]([CH3:44])[CH3:43])/[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH3:1][C@@H:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([NH:48][C@@H:47]([C:49]([CH3:52])([CH3:50])[CH3:51])[C:46]([N:45]([CH3:54])[C@@H:41]([CH:42]([CH3:43])[CH3:44])/[CH:40]=[C:34](\[CH3:33])/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:53])=[O:5]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)(C)C
Reactant: C[C@H](C(=O)O)C(C)(C)c1ccccc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](C)C(C)(C)c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
To a cooled (0° C., ice bath) solution of (2S)-2,3-dimethyl-3-phenylbutanoic acid (0.11 g, 0.57 mmol, from Reference Example 25), hydroxybenzotriazole (93 mg, 0.69 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (0.15 g, 0.80 mmol) in anhydrous dimethylformamide (2 ml) is added N-methylmorpholine (95 uL, 0.86 mmol) via syringe under an inert atmosphere. After stirring for 15 minutes at 0° C., the cooling bath is removed, and the resulting mixture is stirred for 1 hour. The solution is cooled at 0° C. (ice water bath), and to this mixture is added a solution of ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate hydrochloride (0.56 mmol) in anhydrous dimethylformamide (2 ml). The cooling bath is removed, and the resulting mixture is stirred for 22 hours at room temperature under an inert atmosphere. The mixture is diluted with water, and the aqueous layer is extracted with ethyl acetate (3 times). The combined extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed (silica gel, flash column), to provide a white foam (0.20 g, 71%). MS (ES+): (M+H)=487.0
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[S:15][C:14]([CH2:16][NH2:17])=[N:13][N:12]=1>>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:17][CH2:16][C:14]2[S:15][C:11]([CH3:10])=[N:12][N:13]=2)[CH:7]=1
Reactant: Cc1nnc(CN)s1
Reactant: Cc1nc(Cl)cc(Cl)n1
Product: Cc1nc(Cl)cc(NCc2nnc(C)s2)n1

Procedure:
The title compound was prepared from 4,6-dichloro-2-methylpyrimidine and (5-methyl-1,3,4-thiadiazol-2-yl)methanamine according to the protocol outlined in Example 1, to afford 8-1 as a solid. LRMS (ES) (M+H)+: observed=256.1, calculated=256.7.
Reaction SMILES: Cl[O-].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1>O>[N:4]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[N:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: Nc1ccncc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: c1cc(N=Nc2ccncc2)ccn1
Reaction time: 2 h

Procedure:
Sodium hypochlorite, 1000 ml (5.25%, 0.72 mole) was added dropwise to a cold solution (5° C.) of 50 g (0.5 mole) of 4-aminopyridine in 400 ml water. The sodium hypochlorite was added at such a rate as to maintain the reaction temperature at less than 10° C. After the addition was completed, the reactants were stirred for an additional 11/2 hours at ~10° C. The resultant suspension was filtered and air dried to leave a crude brown solid. Recrystallization from methylcyclohexane yielded light orange crystals of 4,4'-azodipyridine, having a m.p. of 87°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20].[NH:21]1[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]1.CC(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH2:15][N:21]2[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20]
Reactant: O=C(O)C1CNC1
Reactant: CC[C@@H](Nc1cccc(C=O)c1)c1ccc(Cl)c(C)c1
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H](Nc1cccc(CN2CC(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of INT 7 (700 mg, 2.43 mmol) and azetidine-3-carboxylic acid (248 mg, 2.92 mmol) in MeOH (24 mL) was added HOAc (0.14 mL, 2.43 mmol) followed by PS—CNBH3 (2.5 mmol/g, 1.95 g, 4.86 mmol). The reaction mixture was stirred at room temperature for 3 days. The mixture was filtered over Celite. The filtrate was concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to give the title compound Example 3.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[I-:19]>CC(=O)CC>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][I:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: BrCCCC(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCCC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 1,1-diphenyl-4-bromobutane (2.5 g, 12 mmol) and NaI (11.9 g, 80 mmol) in 2-butanone (70 ml) was heated for 4 hours at reflux. The solvent was removed in vacuo and the residue was taken up in Et2O (100 ml). The organic layer was washed with aqueous Na2SO3 (10%) and with brine, dried (Na2SO4), and concentrated in vacuo. The oil was distilled under high vacuum to obtain the title compound, bp 150° C./0.1 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:25])[CH:3]=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:38]>CO>[ClH:38].[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:37])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reactant: O=C=NC(=O)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of 194 (93 mg, 0.26 mmol, scheme 40) and 2-phenylacetyl isocyanate (83 mg, 0.62 mmoL) [J. Hill et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and eluted with EtOAc. A white solid was obtained, which was suspended in MeOH and treated with HCl (1 mL, 1.0M in Et2O) to form a clear solution. The solution was concentrated to form a precipitate which was collected by filtration, to afford the title compound 305a (48 mg, 33% yield) as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.05 (s, 1H), 10.62 (s, 1H), 8.57(d, 1H), 8.02 (s, 1H), 7.81(d, 1H), 7.48-7.43 (m, 2H), 7.33-7.25 (m, 5H), 6.74(d, 1H), 3.85(t, 2H), 3.78 (s, 2H), 3.51(t, 2H), 1.98-1.86(m, 2H). MS (m/z): 519.2 (M+H) (found).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[OH:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>C1COCC1>[Br:12][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:15](=[O:16])[C:14]([F:21])([F:20])[F:13])[CH:11]=[CH:10][CH:9]=1
Reactant: NCCC(O)c1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-amino-1-(3-bromophenyl)propan-1-ol (146) (2.30 g, 10 mmol) in anhydrous THF (20 mL) was added ethyl trifluoroacetate (4.0 mL, 33.5 mmol). The reaction mixture was stirred at room temperature for 3 h, then concentrated under reduced pressure. Purification by column chromatography (10 to 70% EtOAc-hexanes gradient) gave N-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (147) as an oil containing 15% of 2,2,2-trifluoro-N-(3-hydroxy-3-phenylpropyl)acetamide. Yield (1.96 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.51 (t, J=2.0 Hz, 1H), 7.41 (dt, J=7.6, 2.0 Hz, 1H), 7.25-7.32 (m, 2H), 5.46 (d, J=6.4 Hz, 1H), 4.55-4.60 (m, 1H), 3.20-3.23 (m, 2H), 1.75-1.82 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[O:18][CH3:19])#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:5][C:4]=1[O:18][CH3:19])#[N:2]
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)OC(C)(C)C)ccc1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)OC(C)(C)C)ccc1C#N
Yield: 99.2 %

Procedure:
To a solution of tert-butyl 3-(4-cyano-3-methoxyphenyl)acrylate obtained in step 1 (3.5 g) in ethyl acetate (150 mL) was added palladium on carbon (500 mg) and the mixture was put under a pressure of 4 kg of hydrogen for 12 h at RT. The catalyst was removed by filtration and the solvents were removed under vacuum to afford the title compound as white solid (3.5 g, 97%). 1H-NMR (CDCl3, 400 MHz) δ 7.41-7.43 (1H, s), 6.80-6.83 (2H, m), 3.88 (3H, s), 2.89-2.93 (2H, t), 2.51-2.55 (2H, t), 1.34 (9H, s). LC/MS: 279.1 (M+H)+. HPLC (Method C) Rt 2.40 min (Purity: 99.7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4](NN)[N:3]=1.[OH-].[Na+].Cl[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: NNc1nc(Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 88 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 53.1 grams (0.25 mole) of 2,3,5-trichloro-6-hydrazinopyridine, 250 milliliters of toluene and 500 milliliters of 1.0N sodium hydroxide, under reflux at 88° C., was added over a 20 minute period 350 milliliters of 6.25 percent sodium hypochlorite. After the addition was complete, the mixture was stirred for an additional 10 minutes and then cooled to room temperature. The organic (toluene) phase was separated and concentrated and cooled. The 2,3,5-trichloropyridine was recovered in a yield of 45.3 grams (99.3 percent of theoretical) and had a purity of 97.6 percent. The product was recrystallized from hexane, filtered through activated carbon and was found to melt at 48°-48.5° C. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 32.78, 1.05 and 7.75 percent, respectively, as compared with the theoretical contents of 32.91, 1.10 and 7.68 percent, respectively, as calculated for the above-named compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:18])[C:15]=1[O:16][CH3:17])[CH2:5][NH:6][C:7](=[S:12])[NH:8][NH:9][CH:10]=O.[O-]CC.[Na+].[Na]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:18])[C:15]=1[O:16][CH3:17])[CH2:5][N:6]1[CH:10]=[N:9][N:8]=[C:7]1[SH:12]
Reactant: COc1c(F)cc(CNC(=S)NNC=O)cc1F
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: COc1c(F)cc(Cn2cnnc2S)cc1F
Yield: 64.5 %

Procedure:
The crude 4-(3',5'-difluoro-4'-methoxybenzyl)-1-formyl-3-thiosemicarbazide (7.3 g) was refluxed overnight in a solution of sodium ethoxide (from sodium (0.3 g) in ethanol (25 ml). The reaction was filtered, evaporated to dryness, and diluted with water. The aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid, and the precipitate was collected by filtration and recrystallized from ethanol-hexane to yield 4.4 g (65%) of 4-(3',5'-difluoro-4'-methoxybenzyl)-1,2,4-triazole-3-thiol, m.p.: 124°-126° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]2[N:15]=[C:16]([C:18]3[C:27]([CH3:28])=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:17]=[C:4]2[N:3]=1.[C:29]1(B(O)O)[CH2:33][CH2:32][CH2:31][CH:30]=1.[F-].[Cs+].O>COCCOC.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>[C:29]1([C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:5]3[N:15]=[C:16]([C:18]4[C:27]([CH3:28])=[N:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:17]=[C:4]3[N:3]=2)[CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: OB(O)C1=CCCC1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: Cc1nc2ccccc2nc1-c1cc2nc(C3=CCCC3)cc(NC3CCOCC3)n2n1
Temperature: 80 °C

Procedure:
A suspension of 5-chloro-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (Example 1.001 (g)) (97 mg, 0.246 mmol), cyclopenten-1-ylboronic acid (55 mg, 0.491 mmol), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.0493 mmol), and cesium fluoride (112 mg, 0.737 mmol) in 1,2-dimethoxyethane (2.0 mL) was heated at 80° C. for 3 h. After being cooled to ambient temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 2:3) to give 5-cyclopent-1-en-1-yl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (the compound of Example 1.011 listed in the Table of Examples as described hereinafter). 1H-NMR (400 MHz, CDCl3): δ 1.73-1.86 (2H, m), 2.03-2.21 (4H, m), 2.60-2.66 (2H, m), 2.86-2.93 (2H, m), 3.05 (3H, s), 3.61 (2H, ddd, J=11.8, 11.8, 2.4 Hz), 3.77-3.87 (1H, m), 4.10 (2H, ddd, J=11.8, 3.3, 3.3 Hz), 6.19 (1H, s), 6.33 (1H, d, J=8.2 Hz), 6.68 (1H, s), 7.08 (1H, s), 7.72-7.79 (2H, m), 8.04-8.08 (1H, m), 8.17-8.21 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15](=[O:29])[N:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[N:18]=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[NH:12][N:11]=2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>N1C=CC=CC=1>[CH3:30][S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15](=[O:29])[N:16]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[N:18]=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[NH:12][N:11]=2)=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of 3-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (38 mg, 0.10 mmol, prepared in Example 13) in pyridine (2 ml) was added methanesulfonyl chloride (18.5 mg, 0.16 mmol, 1.6 eq.), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(4-methanesulfonylaminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (43 mg, 86%).