Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C)C=O.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>O1CCCC1>[NH:18]1[C:17]([NH:16][C:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)=[O:10])=[N:21][N:20]=[N:19]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccnc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccnc(C(=O)Nc2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of 1.06 g of 4-methyl-2-pyridinecarboxylic acid, 1.28 g of N,N'-carbonyldiimidazole, 25 ml of dimethylformamide and 12 ml of tetrahydrofuran is stirred at room temperature for 3 hours. 0.72 g of 5-aminotetrazole is added to the mixture and said mixture is stirred at 80° C. for 3 hours. Then, the reaction mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is adjusted to pH 2 with 10% hydrochloric acid. The crystalline precipitates are collected by filtration, washed with water and then recrystallized from a mixture of dimethylformamide and water. 0.52 g of N-(5-tetrazolyl)-4-methyl-2-pyridinecarboxamide is thereby obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:29])[NH:8][C:9]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][C:13]=1[O:26][CH3:27])([O-])=O>C(O)(=O)C.[Pd]>[CH3:27][O:26][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[C:11]1[N:10]=[C:9]2[NH:8][C:7](=[O:29])[CH2:6][CH:5]=[C:4]2[N:1]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C(=O)Nc1[nH]c(=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(O)ccc1C1=NC2=CCC(=O)NC2=N1
Temperature: 100 °C
Reaction time: 1.3 h

Procedure:
3.95 g of 5-nitro-6-(2-methoxy-4-benzyloxy-benzoylamino)-2-pyridone were hydrogenated in 350 ml of glacial acetic acid after the addition of 1 g of 10% palladium-on-charcoal for 1.7 hours at 80° C. under a pressure of 5 bar. The reaction mixture was then stirred at 100° C. for 1.3 hours. The catalyst was filtered off, and the filtrate was allowed to cool. The product which precipitated was washed with ether. By evaporating the filtrate and adding ether, further fractions were obtained.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[Cl:7][C:8]1[CH:34]=[CH:33][C:11]2[CH:12]=[C:13]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])[CH2:14][O:15][C:10]=2[CH:9]=1.Cl.Cl[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[Cl:7][C:8]1[CH:34]=[CH:33][C:11]2[CH:12]=[C:13]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:41]5[CH:40]=[CH:39][N:38]=[CH:37][CH:42]=5)[CH2:30][CH2:31]4)[C:21](=[O:32])[CH2:20]3)(=[O:17])=[O:18])[CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: Clc1ccccn1
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 39.9 %

Procedure:
To sodium bicarbonate solution were added 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (1.4 g) and chloropyridine hydrochloride (1.02 g), and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (50 ml), and the mixture was allowed to react at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=20:1) to give colorless solid@ 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (608 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].Cl>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(N2CCNCC2)c1F
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 1-[2-fluoro-3-(methylsulfonyl)phenyl]piperazine (0.13 g, 0.52 mmol), acetonitrile (4 ml), potassium carbonate (014 g, 1.1 mmol) and 1-iodopropane (0.05 ml, 0.55 mmol). Yield: 0.1 g (64%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 241-243° C. MS m/z (relative intensity, 70 eV) 300 (M+, 18), 272 (14), 271 (bp), 228 (11), 70 (49).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28]CC1C=CC=CC=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])[CH3:2]
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCO
Reaction time: 4 h
Yield: 78.9 %

Procedure:
Non-polydispersed benzyl ether 18 (1.03 g, 2.0 mmol) was dissolved in 25 ml ethanol. To this solution was added 270 mg 10% Pd/C, and the mixture was placed under a hydrogen atmosphere and stirred for four hours, at which time TLC showed the complete disappearance of the starting material. The reaction mixture was filtered through Celite 545 to remove the catalyst, and the filtrate was concentrated in vacuo to yield the non-polydispersed title compound as a clear oil (0.67 g, 79%). FAB MS: m/e 425 (M+H), 447 (M+Na).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[H-].[Na+].CS([C:15]1[N:16]=[C:17]([O:41][CH2:42][CH2:43][CH3:44])[C:18]2[N:23]=[C:22]([C:24]3[CH:38]=[C:37]([CH3:39])[C:27]([O:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:26]([CH3:40])[CH:25]=3)[O:21][C:19]=2[N:20]=1)(=O)=O>CN(C)C=O>[F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:15]1[N:16]=[C:17]([O:41][CH2:42][CH2:43][CH3:44])[C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[C:26]([CH3:40])[C:27]([O:28][CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[C:37]([CH3:39])[CH:38]=3)[O:21][C:19]=2[N:20]=1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Reactant: O[C@@H]1CCCC[C@H]1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon and at 0 C, 26 mg of trans-2-fluorocyclohexanol were added to a suspension of 10 mg of sodium hydride (60% in mineral oil) in 2 ml of N,N-dimethylformamide. After 15 min, a solution of 100 mg of tert-butyl [4-(5-methanesulfonyl-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate in 1 ml of N,N-dimethylformamide was slowly added. After 12 h at room temperature, the mixture was quenched by addition of water and extracted twice with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure. This gave 101 mg of the title compound.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])=[CH:27][CH:26]=1.[OH-].[Na+]>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:33]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:34]=2)([OH:35])[CH3:32])=[CH:29][CH:30]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC(C)(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(O)(c1ccc(F)cc1)c1cnnn1C1CCc2c(CC(=O)O)c3ccccc3n2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 2-(4-fluorophenyl)but-3-yn-2-ol. Separation of the resulting diastereoisomers was performed at the ester stage by flash chromatography using a gradient of 10-70% EA/Hex afforded two enantiomeric mixtures. The faster eluting enantiomeric mixture was resolved on chiral HPLC using a 50×400 mm Chiralcel OD column eluting with 8% iPrOH, 8% EtOH, 83.75% Hexanes and 0.25% Et3N at 60 mL/min and 254 nm. The resulting esters (retention times=18.4 and 22.1 min) were hydrolyzed separately in THF/MeOH (2:1, 0.1M) at room temperature using 1M solution of sodium hydroxide (10 eq). The reaction mixture was stirred at room temperature for 2 h then quenched by adding HCl 10% until acidic pH and diluted with DCM. Filtration through a phase separator followed by evaporation afforded the desired EXAMPLE 5.1 and 5.2 respectively. The slower eluting enantiomeric mixture was resolved on chiral HPLC using a 50×400 mm Chiralcel OD eluting with 30% iPrOH, 70% Hexanes at 60 mL/min and 254 nm. The resulting esters (retention times=18.3 and 34 min) were hydrolyzed in a similar fashion as described above to afford EXAMPLE 5.3 and 5.4 respectively. 1H NMR data is for EXAMPLE 5.1: 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.97 (s, 1H), 7.45 (d, 1H), 7.36 (dd, 2H), 7.31 (d, 1H), 7.20 (t, 2H), 7.11-7.00 (m, 2H), 6.68 (s, 1H), 5.03 (s, 1H), 4.54 (dd, 1H), 4.24 (t, 1H), 3.60-3.48 (m, 2H), 3.01-2.91 (m, 1H), 2.37-2.26 (m, 1H), 2.02-1.93 (m, 1H), 1.90 (s, 3H), 1.36-1.24 (m, 1H). MS (+ESI) m/z: 435.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:9]2[CH2:10][S:11](=[O:14])[CH2:12][CH2:13][C:8]=2[S:7][C:6]=1[C:15]([OH:17])=O)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>CN(C=O)C>[NH:32]1[C:31]([NH:30][C:15]([C:6]2[S:7][C:8]3[CH2:13][CH2:12][S:11](=[O:14])[CH2:10][C:9]=3[C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[O:17])=[N:35][N:34]=[N:33]1
Reactant: CC(C)Oc1c(C(=O)O)sc2c1CS(=O)CC2
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CS(=O)CC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
To a stirred solution of 0.494 g (1.8 mM) of 3-isopropoxy-5-oxo-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid (from Preparation 13) in 10 mL of DMF were added 0.438 g (2.7 mmol) of 1,1'-carbonyldiimidazole. The reaction mixture was heated at 80° C. for 60 minutes, followed by addition in one portion of 0.283 g (3.33 mmol) of 5-aminotetrazole. The reaction mixture was heated at 80° C. for 5 hours, cooled to 24° C., and stirred for an additional 18 hours. The mixture was concentrated to dryness by evaporation of the solvent under reduced pressure. The residue was dissolved in 100 mL of chloroform, washed with 2N HCl, water, brine, dried over MgSO4, and the solvent was removed by evaporation under reduced pressure. The solid residue was recrystallized from methanol/diethyl ether to afford 0.279 g of 3-isopropoxy-5-oxo-6,7-dihydro-4H-thieno[3,2-c] thiopyran-2-carboxylic acid (1H-tetrazol-5-yl) amide, mp 225°-226° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([Sn](C)(C)C)=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1.Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:33]([CH3:35])=[CH:34][C:27]=12>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.CN(C=O)C>[F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]4[N:32]([S:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:37])=[O:38])[C:33]([CH3:35])=[CH:34][C:27]=34)=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: C[Sn](C)(C)c1cc(N)c2c(F)nn(S(=O)(=O)c3ccccc3)c2c1
Reactant: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc2c(-c3cc(N)c4c(F)nn(S(=O)(=O)c5ccccc5)c4c3)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 1.33 h

Procedure:
3-Fluoro-1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (660 mg), Pd(PPh3)4 (168 mg) and 4-bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (613 mg) were weighed into a microwave vial and DMF (10 ml) was added. The mixture was heated to 120° C. overnight. The mixture was then cooled to RT and the solvent was removed in vacuo. The crude material was dried in a vacuum oven overnight. The resulting dark brown oil was purified by FlashMaster II. The crude material was dissolved in chloroform and added to the top of 2×100 g silica SPE cartridges that were subsequently eluted with 0-100% ethyl acetate:cyclohexane over 80 min. The product-containing fractions were combined and the solvent removed in vacuo to give the title compound, 357 mg as a cream solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].[Cl:26][CH:27]=[CH:28][CH2:29]Cl>CN(C=O)C.[Na+].[Cl-]>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]([CH2:29][CH:28]=[CH:27][Cl:26])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(S(C)(=O)=O)ccc2c1Br
Reactant: ClC=CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2cc(S(C)(=O)=O)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
A stirred suspension of 162 (4.70 g, 11.74 mmol) in dry DMF (40 mL) was treated portionwise at 0° C. with NaH (564 mg, 60% in oil, 14.10 mmol). The mixture was warmed to room temperature for 1 h then cooled to O—C and treated with 1,3-dichloropropene (3.4 mL, 37 mmol, mixed isomers). The mixture was stirred at room temperature for a further 6 h, then diluted with 10% aqueous NaCl and extracted with EtOAc (×2). The combined organic layers were washed with water (×2), dried, and concentrated to dryness under reduced pressure at 100° C. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (9:1) to give tert-butyl 1-bromo-6-(methylsulfonyl)-2-naphthyl(3-chloro-2-propen-1-yl)carbamate (163) (5.41 g, 970%) as a foam; 1H NMR [(CD3)2SO] (mixture of rotamers and E and Z forms) δ 8.73-8.69 (m, 1H), 8.46 (d, J=9.0 Hz, 1H, 8.30, 8.29 (2 d, J=8.6 Hz, 1H), 8.14 (dd, J=9.0, 1.8 Hz, 1H), 7.71, 7.68 (2 d, J=8.6 Hz, 1H), 6.43-6.28 (m, 1H), 6.19-6.01 (m, 1 H), 4.59-4.48, 4.44-4.23, 4.19-4.05 (3 m, 2H), 327 (after D2O exchange, s, 3H), 1.50, 1.26 (2 s, 9H). HRMS (FAB) calcd. for C19H2279Br35ClNO4S (MH+) m/z 474.0141, found 474.0142.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[Cl:12])[CH3:2].[CH:14]1(B(O)O)C[CH2:15]1>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]2[CH2:15][CH2:14]2)[C:6]=1[Cl:12])[CH3:2]
Reactant: CCOC(=O)c1ccnc(C)c1Cl
Reactant: OB(O)C1CC1
Product: CCOC(=O)c1ccnc(C2CC2)c1Cl

Procedure:
This compound was prepared using a method analogous to that of 3-chloro-2-methylisonicotinic acid ethyl ester (A.2.5.2), cyclopropylboronic acid replacing trimethylboroxine. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (9/1) gives the desired product as colorless oil;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C[CH2:20][N:21](C(C)C)C(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Yield: 34.3 %

Procedure:
A solution of 2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (300 mg, 1.001 mmol), methanamine, HCl salt (135 mg, 2.003 mmol) and DIPEA (0.700 mL, 4.01 mmol) in MeOH (6 mL) was stirred at rt for 30 min. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (101 mg, 0.343 mmol, 34.3% yield). LC-MS (M+H)+=294.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13](=[O:20])[C:14]3[S:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:16][C:15]2[CH:17]=[CH:18][S:19][C:14]=2[C:13]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc3ccsc3c(=O)o2)cc1
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2sccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 40.8 %

Procedure:
A solution of 2-[4-(tert-butyl)phenyl]-4-oxo-4H-thieno[3,2-d] [1.3]oxazine (60 mg, 0.21 mmol) and p-anisidine (26 mg, 0.21 mmol) in toluene (1 mL) was treated with p-toluenesulfonic acid (4 mg) and the resulting mixture heated at relux for 30 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate) to yield 35 mg (41%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: Cc1cnc(N2CCC(=O)CC2)cn1
Product: Cc1cnc(N2CCC(NC3CC3)CC2)cn1

Procedure:
The title compound is prepared from 1-(5-methyl-pyrazin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 1): tR=0.68 min; Mass spectrum (ESI+): m/z=233 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]([Cl:15])([Cl:14])[C:8]1[N:12]=[C:11](Cl)[S:10][N:9]=1>CCOCC>[Cl:6][C:7]([Cl:15])([Cl:14])[C:8]1[N:12]=[C:11]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:10][N:9]=1
Reactant: C1CCNC1
Reactant: Clc1nc(C(Cl)(Cl)Cl)ns1
Solvent: CCOCC
Product: ClC(Cl)(Cl)c1nsc(N2CCCC2)n1
Reaction time: 1 h

Procedure:
To 14.2 grams (0.2 mole) pyrrolidine in 100 milliliters ether was added 23.8 grams (0.1 mole) 3-trichloromethyl-5-chloro-1,2,4-thiadiazole in 100 milliliters ether. The solution was refluxed with stirring for one hour after addition. Filtration to remove salt by-products yielded a clear filtrate which was concentrated on a steam bath to give 16.4 grams (60% molar yield) of white solid. Recrystallization from ligroin yielded a pure product (melting point 105.5°-107° C.). The structure was confirmed via infrared and elemental analysis. Analysis for C7H8N3Cl3S:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ncc2cccc(-c3ccc(C#N)cc3)n12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ncc2n1C(c1ccc(C#N)cc1)CCC2

Procedure:
A solution of 1.1 g of 5-(p-cyanophenyl)-3-ethoxycarbonyl-imidazo[1,5-a]pyridine in 30 ml of ethanol is hydrogenated with 0.1 g of 10% Pd on charcoal at 1 bar for 2 h, filtered and evaporated to dryness. The resulting oil is partitioned between water and ethyl acetate. The organic phase is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on 40 g of silica gel with ethyl acetate to yield 5-(p-cyanophenyl)-3-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([O:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=4)[N:9]=[CH:8][N:7]=3)[CH:3]=2)=[O:33])[CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1O
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (2.0 g, ˜0.0070 mol) in DMF (10 mL), phenyl 5-tert-butylisoxazol-3-ylcarbamate (1.74 g, 0.0067 mol) was added. The reaction mixture was stirred at 60° C., overnight. The solvent was evaporated under vacuum and the residue was sonicated in the presence of ethyl ether (60 mL). The solid was filtered and washed with ethyl ether to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (2.75 g, 87.5% yield). 1HNMR (DMSO-d6): δ 10.53 (s, 1H), 9.57 (s, 1H), 8.99 (s, 1H), 8.50 (s, 1H), 7.52 (d, 2H), 7.37 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.18 (s, 1H), 4.00 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
Compound 1 (150 mg, 0.32 mmol) was dissolved in DCM and TFA (0.25 mL, 3.20 mmol) was added. The resulting mixture was stirred overnight. The mixture was concentrated, diluted with DCM and washed with saturated NaHCO3 solution. The filtrate was dried anhydrous Na2SO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with 0-30% 1M methanolic ammonia/dichloro-methane to give desired product, Compound 2 as a white solid (0.10 g, 85%). MS: m/z 370.2 [M+H]+. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.76 (s, 3H), 3.16 (m, 2H), 4.11 (m, 2H), 4.37 (m, 3H), 7.53 (m, 3H), 7.71 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[C:3]1=[O:18].[ClH:19]>C(OCC)(=O)C>[ClH:19].[NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:10][C:11]([OH:13])=[O:12])[C:3]1=[O:18]
Reactant: CC(C)(C)OC(=O)CN1CCCCCC(N)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCCCCN(CC(=O)O)C1=O

Procedure:
3-Amino-1-t-butoxycarbonylmethylperhydroazocin-2-one is treated with 4N HCl in ethyl acetate to afford 3-amino-1-carboxymethylperhydroazocin-2-one hydrochloride. An aqueous solution of this hydrochloride and 3-5 equivalents of an α-ketoacid from Table III is adjusted to pH 6.5 with sodium hydroxide and treated with 3 equivalents of sodium cyanoborohydride for 18 hours. The product is absorbed on a strong acid ion exchange resin and eluted with 5% pyridine in water. Lyophilization affords the products of Formula I listed in Table II in which R2, R3 =H and R, R4 =OH.