Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:45])[C@@H:13]([NH:15][C:16]([C:18]2[N:22]3[C@@:23]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=4)([CH3:35])[C:24](=[O:34])[N:25]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:21]3=[N:20][CH:19]=2)=[O:17])[CH3:14])[CH2:7]1)=O)C.[NH3:46]>CO>[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:45])[C@@H:13]([NH:15][C:16]([C:18]2[N:22]3[C@@:23]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=4)([CH3:35])[C:24](=[O:34])[N:25]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)[C:21]3=[N:20][CH:19]=2)=[O:17])[CH3:14])[CH2:7]1)(=[O:3])[NH2:46]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)C1
Reactant: N
Solvent: CO
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](C(N)=O)C1
Temperature: 70 °C

Procedure:
(R)-1-((S)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionyl)-piperidine-3-carboxylic acid ethyl ester was dissolved in 7N NH3 in MeOH (5 mL) and heated to 70° C. for 48 h. The volatiles were removed in vacuo and the crude residue was purified by reverse phase HPLC to afford 0.049 g of the title compound as a white foam, m/z 622.3 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=O)[CH2:18][CH2:17]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:24][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:20][CH2:21]1
Reactant: Cn1c(OC2CCN(c3ccccc3C=O)CC2)nc(-c2ccncn2)cc1=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(OC2CCN(c3ccccc3CN3CCOCC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of 2-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]benzaldehyde (80 mg, 0.20 mmol), morpholine (27 mg 0.31 mmol) and acetic acid (one drop) in 1,2-dichloroethane (1.0 ml) was added sodium triacetoxyborohydride (110 mg, 0.52 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol=95/5) to afford 1-methyl-2-[1-(2-morpholin-4-ylmethyl-phenyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (63 mg, 0.14 mmol, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1.Cl.[N-:18]=[N+:19]=[N-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[N:1]([C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1)=[N+:18]=[N-:19]
Reactant: CCN(CC)CC(=O)Nc1cccc(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)Nc1cccc(N=[N+]=[N-])c1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
N-(3-Aminophenyl)-2-(diethylamino)acetamide 5 (0.52 g, 2.35 mmol) was dissolved in THF (6 ml), and cooled in an ice bath. The resulting stirred mixture was treated sequentially with concentrated aqueous HCl (1.08 ml, 12.92 mmol), then with tBuONO (0.61 g, 5.87 mmol). The reaction was stirred in an ice bath for 1.5 hours and after that time NaN3 (0.46 g, 7.05 mmol) was added, followed by careful addition of water, until the reaction ceased to effervesse. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was carefully neutralised with saturated aqueous NaHCO3 solution and THF was evaporated in vacuo. The aqueous solution was extracted three times with EtOAc (75 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo, to give N-(3-azidophenyl)-2-(diethylamino)acetamide 6 as a dark brown oil (0.56 g, 85%) without requiring any further purification; Rf 0.24 [10% MeOH in DCM]; IR (film): 3279.67, 2934.63, 2110.57, 1687.86, 1515.73 cm−1; δH (CDCl3, 400 MHz) 9.43 (1H, s, NH), 7.41 (1H, m, ArH), 7.30-7.23 (2H, m, 2×ArH), 6.76 (1H, td, J1=8.0, J2=2.0 Hz, ArH), 3.13 (2H, s, CH2), 2.64 (4H, m, 2×CH2), 1.08 (6H, m, 2×CH3); δC (CDCl3, 100 MHz) 170.25 (C═O), 140.95 (Ar—C), 139.18 (Ar—C), 130.14 (Ar—CH), 115.60 (Ar—CH), 114.48 (Ar—CH), 109.96 (Ar—CH), 58.11 (CH2), 48.92 (2×CH2), 12.40 (2×CH3); LC-MS (5 min) m/z 248.49 [C12H17N5O+H]+ (25), 220.07 [(C12H17N5O+H)-28]+ (40) Rt 2.05 min; HRMS m/z calc. C12H18N5O [M+H]+248.1506. found [M+H]+ 247.1498.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]([C:10]#[N:11])[CH2:5][CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:11][CH2:10][CH:4]1[CH2:5][CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]1[CH2:9][CH2:8]2
Reactant: CN1C2CCC(C#N)C1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C2CCC(CN)C1CC2
Reaction time: 3 h

Procedure:
The nitrile (1.1 g) in tetrahydrofuran (20 ml) was added to lithium aluminium hydride (0.5 g) in tetrahydrofuran (30 ml) and the mixture stirred for three hours. Water (0.5 ml) sodium hydroxide solution (10%) (0.75 ml) and water (1.25 ml) were added successively and the mixture filtered. The filtrate was dried (K2CO3) and evaporated to give crude (D31) (1 g) as an oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2ccccc2N1
Agent: O=S(=O)(O)O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,4-dihydroquinolin-2-(1H)-one (1.50 g) in 78% sulfuric acid (300 mL) at RT, a mixture of 69% nitric acid (0.84 mL) in 78% sulfuric acid (60 mL) was added. The reacting mixture was stirred at RT for 15 min, poured into ice-water, and extracted with methylene chloride (3×200 mL). The organic extracts were combined, washed with brine (4×), dried over anhydrous magnesium sulfate, filtered and concentrated onto silica gel. The residue was loaded onto a column of silica gel, and eluted with 3% methanol in chloroform. Collection and concentration of appropriate fractions provided the nitroquinolinone 11-2.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].F[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[CH2:21]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:20]1[CH:23]=[CH:24][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of Compound 11 (5 g, 28 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added, and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 6.3 g (79%) of white solids. M.P. 153° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 5.24 (s, 2H), 7.14-7.17 (m, 3H), 7.44 (m, 2H), 7.54 (dd, J=1.7, 8.2 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H). Anal. (C16H12FNO3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]2[CH:22]=[C:23]([S:26](Cl)(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18]1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:23]1[CH:24]=[CH:25][C:20]2[CH2:19][CH2:18][O:17][C:21]=2[CH:22]=1)(=[O:27])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCC2
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc2c(c1)OCC2

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 109 mg of 2,3-dihydro-benzofuran-6-sulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.80 (t, 2H, J=8.8 Hz), 4.42 (t, 2H, J=9.2 Hz), 6.57 (d, 1H, J=8.4 Hz), 7.35 (m, 3H), 7.43 (m, 3H), 7.48 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.6 (m, 1H), 7.74 (d, 1H, J=8.8 Hz), 9.48 (s, 1H). MS: m/z 414.9 (M++1).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1>C1COCC1>[CH2:3]([O:9][C:11]1[C:15]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1ccc(-c2nsnc2Cl)cn1
Reactant: CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCOc1nsnc1-c1ccc(C)nc1
Reaction time: 2 h

Procedure:
Sodium hydride (0.72 g, 15 mmol) was dissolved in dry THF (20 ml) and 1-hexanol (1.53 g, 15 mmol) and a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-6-methylpyridine (1.06 g, 5 mmol) in dry THF (15 ml) was added. The reaction mixture was stirred for 2 h. Afteraddition of water the mixture was extracted with ether, and the ether phasewas dried and evaporated. The residue consisted of the crude title compound, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH3:27])[CH:15]=3)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(Cl)cc2)c1

Procedure:
Prepared according to the procedure used for the preparation of Intermediate 23, starting from ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (200 mg, 0.46 mmol) and 4-chlorobenzene boronic acid (86 mg, 0.55 mmol) to give, after purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with petroleum ether 40-60° C.:EtOAc (19:1), the title compound (137 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([NH:16][NH2:17])=O)=O)(C)(C)C.[O:18]=[C:19]1[NH:24][C:23]2[CH:25]=[C:26]([C:29](N)=[NH:30])[CH:27]=[CH:28][C:22]=2[O:21][CH2:20]1.C(O)(=O)C>CN(C=O)C>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[NH:16][N:17]=[C:29]([C:26]2[CH:27]=[CH:28][C:22]3[O:21][CH2:20][C:19](=[O:18])[NH:24][C:23]=3[CH:25]=2)[N:30]=1
Reactant: N=C(N)c1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1COc2ccc(-c3n[nH]c(C4CCCCN4)n3)cc2N1
Temperature: 120 °C

Procedure:
1.5 mmol of 2-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml DMF. 1 eq of 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamidine and 90 ul acetic acid were added and the reaction mixture heated to 120° C. overnight. The solvent was evaporated and the crude extracted from ethylacetate/water. The resulting oil was taken up in 15 ml DCM and treated with 3 ml TFA. The reaction mixture was reduced to dryness.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]2[N:10]([CH3:26])[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[O:16])[C:13](=[O:14])[C:8]=2[S:7][C:6]=1[CH:27]=[O:28])=[N+:2]=[N-:3].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:1]([CH2:4][C:5]1[C:9]2[N:10]([CH3:26])[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[O:16])[C:13](=[O:14])[C:8]=2[S:7][C:6]=1[CH2:27][OH:28])=[N+:2]=[N-:3]
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C=O)c(CN=[N+]=[N-])c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)c(CN=[N+]=[N-])c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a cold (0° C.), stirred solution of 230 mg of 3-(azidomethyl)-N-(4-chlorobenzyl)-2-formyl-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 6 mL of CH2Cl2 is added 0.16 mL of acetic acid and 296 mg of sodium triacetoxyborohydride. The ice bath is removed and the solution allowed to stir at room temperature for 2 h. Aqueous workup (CHCl3/aq. NaHCO3) followed by flash chromatography on silica using 3% MeOH in CH2Cl2 affords 150 mg of the title compound as a white solid. Recrystallization from acetonitrile provides off-white crystals.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][CH3:8].[C:15](=S)=[S:16]>C1(C)C(C)=CC=CC=1>[CH3:8][O:7][CH2:6][CH2:5][N:4]1[CH2:3][CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:15]1=[S:16]
Reactant: S=C=S
Reactant: COCCNCC(N)c1ccccc1
Solvent: Cc1ccccc1C
Product: COCCN1CC(c2ccccc2)NC1=S
Temperature: 130 °C

Procedure:
The ethylamine product of Example IV in the amount of 6.85 g is dissolved in 20 ml xylene, and this is then stirred with 3 ml carbon disulfide at room temperature for two hours. The resulting slurry is then slowly heated to 130° C. and maintained at this temperature for four hours.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:4]=2[S:5][C:6]=1[CH:7]=O.[BH4-].[Na+].[CH3:16][NH2:17]>CO>[Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:4]=2[S:5][C:6]=1[CH2:7][NH:17][CH3:16]
Reactant: CN
Reactant: O=Cc1sc2c(F)cccc2c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2c(F)cccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 3-chloro-7-fluoro-benzo[b]thiophene-2-carbaldehyde (610 mg, 2.78 mmol) in CH3NH2 (20 mL of a 2.0 M solution in MeOH, 40 mmol) was stirred at room temperature overnight. The mixture was concentrated. The residue was dissolved in EtOH (20 mL), and after cooling in an ice bath, NaBH4 (159 mg, 4.20 mmol) was added. The mixture was slowly warmed to room temperature and then stirred overnight. The mixture was concentrated. The residue was taken up in NaOH (20 mL) and the mixture extracted with Et2O (3×). The combined organics were washed with satd NaCl, dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, 95:5 CH2Cl2/MeOH) gave the title compound (460 g, 70%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=8.0 Hz, 1H), 7.38 (ddd, J=7.9, 7.9, 4.9 Hz, 1H), 7.06 (dd, J=8.8, 8.8 Hz, 1H), 4.09 (s, 2H), 2.53 (s, 3H), 1.55 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([OH:19])=[CH:14][N:15]2[CH3:18])=[CH:10][CH:9]=1)#[N:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:19][C:13]1[C:12](=[O:20])[C:11]2[C:16](=[CH:17][C:8]([C:6]#[N:7])=[CH:9][CH:10]=2)[N:15]([CH3:18])[CH:14]=1)(=[O:4])=[O:3]
Reactant: Cn1cc(O)c(=O)c2ccc(C#N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(C#N)cc21

Procedure:
Methanesulphonyl chloride (1.0 ml) was added to a stirred suspension of 7-cyano-3-hydroxy-1-methyl-4quinolone (0.4 g) and triethylamine (2.0 ml) in dry dichloromethane (200 ml) at 0 to 5° and the resultant solution stirred for 2 hours. The solution was washed with water (2×50 ml), dried over magnesium sulphate and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (40:1) followed by trituration with diethyl ether (10 ml) to give the novel compound 7-cyano-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 268°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=2[O:34][CH3:35])[N:3]=1.[NH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:45]=1[C:44](=[O:46])[N:43]([CH3:47])[CH2:42]2>>[CH3:35][O:34][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:36][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:45]=2[C:44](=[O:46])[N:43]([CH3:47])[CH2:42]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[O:19][CH2:20][C:21]([F:24])([F:23])[F:22]
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: CN1Cc2cccc(N)c2C1=O
Product: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1Nc1ncc(C(F)(F)F)c(Nc2cccc3c2C(=O)N(C)C3)n1

Procedure:
The title compound was prepared according to the procedure for Example 102 using bis(2,2,2-trifluoroethyl) (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 124A, 67.0 mg, 0.119 mmol) and 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (Preparation XXXVIII, 26.9 mg, 0.166 mmol). The crude product was adsorbed onto a pre-filled solid loading cartridge and purified using the Teledyne/ISCO Combiflash system eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo. The material was further purified by MDP (under basic conditions; ammonium bicarbonate buffer, pH 9), which afforded the title material as an off-white solid, 54.8 mg (64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H), 9.13 (s, 1H), 8.40 (s, 1H), 8.37 (br s, 1H), 7.49 (br d, J=7.1 Hz, 1H), 7.37 (br t, J=7.1 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.60-4.74 (m, 4H), 4.45 (s, 2H), 3.74 (s, 3H), 3.61 (d, J=22.2 Hz, 2H), 3.06 (s, 3H). MS (ES+): m/z 688.08 (100) [MH+]. HPLC: tR=3.72 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:25])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].C[N:32]([CH:34]=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:25])[NH:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:7]=[CH:6][C:34]([NH2:32])=[CH:4][CH:3]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(Nc1cccc(Br)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-(3-Bromo-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (201 mg, 0.5 mmol), 6-4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1 eq., 108 mg), Pd[P(Ph)3]4 (5 mol %, 20 mg), in methanol (6 mL), NaHCO3 (sat. aq., 900 uL) and DMF (1.5 mL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the products. Yield 26 mg. MS: 440.3 (M+H). H1-NMR (DMSO-d6): δ (ppm) 10.1 (s, 1H), 7.9 (m, 1H), 7.5-7.0 (m, 12H), 5.0 (m, 2H), 4.4 (m, 1H), 3.5 (m, 1H), 2.2 (m, 1H), 1.9 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]([CH2:7][CH2:8][CH:9]=[C:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[CH:4][CH2:5]O)[CH3:2].P(Br)(Br)[Br:16]>CCOCC>[Br:16][CH2:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH2:7][CH2:8][CH:9]=[C:10]([CH2:13][CH3:14])[CH2:11][CH3:12]
Reactant: CCC(=CCCC(=CCO)CC)CC
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCC(=CCCC(=CCBr)CC)CC
Reaction time: 2 h

Procedure:
3,7-Diethylnona-2,6-dien-1-ol (4.8 g.) is dissolved in 40 ml. of ether, cooled to -50° and 2.44 g. of phosphorus tribromide in 5 ml. of ether is added over 20 minutes. The reaction mixture is stirred for two hours, poured into ice and extracted with ether. The ethereal extracts are combined, washed with 10% sodium carbonate, water and saturated sodium chloride, dried over sodium sulfate and the solvent concentrated to yield 1-bromo-3,7-diethylnona-2,6-diene.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[NH:5][N:6]=1.[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18](=O)[CH2:19][C:20](OCC)=[O:21])[CH:16]=[CH:17][C:9]1=2>C(O)(=O)C>[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18]3[NH:7][C:4]4[N:5]([N:6]=[C:2]([CH3:1])[N:3]=4)[C:20](=[O:21])[CH:19]=3)[CH:16]=[CH:17][C:9]1=2
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)OCCO2
Reactant: Cc1n[nH]c(N)n1
Solvent: CC(=O)O
Product: Cc1nc2[nH]c(-c3ccc4c(c3)OCCO4)cc(=O)n2n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
A mixture of 5-methyl-2H-1,2,4-triazol-3-amine (147 mg, 1.50 mmol, 1.00 equiv), acetic acid (3 mL), and ethyl 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (375 mg, 1.50 mmol, 1.00 equiv) was stirred for 16 hr at 120° C., then concentrated to dryness. The resulting solid was washed by 5 mL MeOH and collected by filtration. The solid was dissolved in 10 mL of NH4OH (aq.) and filtered. The filtrate was adjusted to pH<5 with HOAc, then concentrated to dryness. The resulting solid was washed by 10 mL water, collected by filtration, and dried to get 50 mg (12%) of 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a yellow solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:23](=[O:24])[C:22]([CH2:28][CH2:29][CH3:30])([CH2:25][CH2:26][CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:31])=O)(=[O:4])=[O:3].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[OH-].[K+]>[O:4]=[S:2]1(=[O:3])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12]([C:14]2[C:23](=[O:24])[C:22]([CH2:28][CH2:29][CH3:30])([CH2:25][CH2:26][CH3:27])[C:21]3[C:16]([C:15]=2[OH:31])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:1]1
Reactant: CCCC1(CCC)C(=O)C(C(=O)Nc2ccccc2S(N)(=O)=O)=C(O)c2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 130 °C
Reaction time: 30 h
Yield: 57.5 %

Procedure:
A suspension of the product of Example 1G (150 mg, 0.34 mmol) in 10% potassium hydroxide solution (9 mL) was stirred at 130° C. for 30 hours, cooled to 25° C., acidified to pH 3 by addition of 1 M citric acid, stirred with ethyl acetate, and filtered through Celite®. The organic layer from the filtrate was washed with saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from ether-hexane solution to afford the title compound (83 mg, 57%). 1H NMR (300 MHz, CDCl3): δ16.70 (s, 1 H), 14.22 (s, 1 H), 8.26 (d, J=8.09 Hz, 1 H), 7.99 (d, J=8.09 Hz, 1 H), 7.67 (m, 1H), 7.47 (m, 3 H), 7.29 (m, 2 H), 2.25 (m, 2 H), 1.86 (m, 2 H), 0.89 (m, 2 H), 0.70 (m, 8 H).