Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:30][C@H:29]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[C@@H:20]([O:21][Si](C(C)(C)C)(C)C)[C@@H:12]2[O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[C:4]([O:40][CH3:41])[N:3]=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>O1CCCC1.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:20]([OH:21])[C@@H:12]2[O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[C:4]([O:40][CH3:41])[N:3]=1
Reactant: CCCCC(=O)O[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(OC)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OC)nc(N)nc21
Temperature: 5 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-O-valeryl-β- D-arabinofuranosyl)-6-methoxy-9H-purine (1.4 g, 2.3 mmol) was taken up in tetrahydrofuran (THF, 40 mL) and cooled in an ice bath to 5° C. Acetic acid (0.06 mL, 10 mmol) was added, followed by tetrabutylammonium fluoride (TBAF) as a 1M solution in THF (10 mL, 10 mmol). After 18 hours at 5° C., the reaction mixture was diluted with CHCl3 (40 mL) and passed through a pad of silica gel (230-400 mesh, 5×5 cm) with 1:1 acetone:CHCl3 (500 mL). The filtrate was concentrated and purified on a Chromatotron fitted with a 4 mm rotor and eluted with neat ethyl acetate. Pure product was obtained from the column as a white foam 0.72 g (78%) after drying and was shown to be the desired 2'-O-valeryl derivative: m.p.: 83°-86° C. (uncorrected); UV λmax (δ): pH=7.00:280.0 nm (7,800), 247.8 nm (8,400); 0.1N HCl: 278.6 (8,000), 248.7 (7,400); 0.1N NaOH: 286.2 (7,600), 244.9 (7,200); MS (El): m/z 381 (C16H23N5O6), 351 (C15H21N5O5), 292 (C13H18N5O3), 279 (C11H13N5O4), 249 (C10H11N5O3), 217 (C10H17O5), 194 (C7H8N5O2), 165 (C6H7N5O), 135 (C5H5N4), 85(C5H9O). IR(KBr) 1745.2, 1613.3 and 1588.7cm-1. 1H-NMR (Me2SO-d6): δ7.93(s, 1H, H-2),6.46(br s, 2H, NH2 ),6.26(d, 1H, H-1', J=5.9Hz), 5.79(d, 1H, 3'-OH, J=5.1 Hz), 5.23 (t, 1H, H-2', J=5.8 Hz), 5.02 (t, 1H, 5'-OH, J=5.6 Hz), 4.36 (ddd, 1H, H-3', J3',3'--OH =5.1 Hz, J2',3' =5.7 Hz, J3',4' =5.8 Hz), 3.93 (s, 3H, Pur-OCH3), 3.83-3.78 (m, 1H, H-4'), 3.68-3.61 (m, 2H, H-5'), 2.09 (dt, 1H, C(O)CH2, J=7.5 Hz, J=15 Hz), 1.93 (dt, 1H, C(O)CH2, J=7.5 Hz, J=15 Hz), 1.30-0.90 (m, 4H, --CH2CH2--), 0.65 (t, 3H, --CH3, J= 7 Hz). Anal. Calcd. for C16H23N5O6.0.15 C5H10O3 : Calcd: C, 50.41; H, 6.22; N, 17.29. Found: C, 50.41; H, 6.59; N, 17.40.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1CCCCC1>[CH2:23]([O:22][C:16](=[O:21])[CH:17]=[C:18]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:20])[CH3:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 9987.2 %

Procedure:
20 g (98.4 mmol)of 3-benyloxyaniline, 12.6 ml (0.984 mmol) of ethyl acetoacetate and 0.189 g (1 mmol) of p-toluenesulfonic acid monohydrate in 32 ml of cyclohexane were heated at reflux for 5.5 h in the presence of a water separator funnel. The reaction mixture was cooled to RT, some solid material was filtered off by suction and the filtrate was concentrated in vacuo to give 30.6 g (99%) of the desired 3-(3-benzyloxy-phenylamino)-but-2-enoic acid ethyl ester as a yellow oil. This was used without further purification in the next reaction step.
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[S:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH3:31])[C:20]3=[S:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: S=c1[nH]c2ccccc2n1C1CCN(C2Cc3cccc4cccc2c34)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=S)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
(RS)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazole-2-thione (1 g, 2.6 mmol) was dissolved in DMF (15 ml) and sodium hydride (120 mg, 60%) was added. The suspension was stirred at 50° C. for 30 min. After cooling to room temperature, methyl iodide (0.4 g, 2.8 mmol) was added and the mixture was stirred for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.05 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=[O:41])[CH2:10][N:11]2[C:15]3=[N:16][C:17]([C:25]4[S:26][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[S:38]([CH3:40])=O)=[CH:28][N:29]=4)=[C:18]([O:21]C(=O)C)[C:19](=[O:20])[N:14]3[CH:13]=[CH:12]2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9](=[O:41])[CH2:10][N:11]2[C:15]3=[N:16][C:17]([C:25]4[S:26][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[S:38][CH3:40])=[CH:28][N:29]=4)=[C:18]([OH:21])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12]2)[CH2:5]1
Reactant: CC(=O)Oc1c(-c2ncc(Cc3ccc(F)cc3S(C)=O)s2)nc2n(CC(=O)N3CC(C)OC(C)C3)ccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CSc1cc(F)ccc1Cc1cnc(-c2nc3n(CC(=O)N4CC(C)OC(C)C4)ccn3c(=O)c2O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of the product of example 171 (38 mg, 0.06 mmol) in MeOH (5 ml) was added K2CO3 (20 mg, 0.14 mmol) and then the mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with dichloromethane. The organic layers were dried and concentrated. The resulting solids were collected and washed with cold MeOH (2-3 ml) to give the title compound (15 mg, yield 42%).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1.CC#N>CN1C(=O)CCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nnc(N3CCNCC3)c3ccccc23)cc1
Reactant: N#Cc1cnc(Cl)nc1
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1

Procedure:
Using the general protocol, 1-benzyl-4-piperazin-1-yl-phthalazine (56 mg, 0.184 mmol) and 2-chloro-5-cyanopyrimidine (44.5 mg, 0.239 mmol) are added into a microwave vial, equipped with a stir bar, and MeCN (0.5 ml) and NMP (0.5 ml) are dispensed. The vial is sealed and the reaction was irradiated at high level absorption in the microwave at 180° C. for 15 min. The product is observed as the main peak (m/z; M+1=408). The compound is purified by preparative HPLC using a C8-254 nm method.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13]([OH:15])=[O:14])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1OCC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)O)cc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of a solution of the product of step (b) (34.6 g) in ethyl acetate (600 ml) and 10% palladium/carbon (3 g) was stirred under an atmosphere of hydrogen for 5 hours at ambient temperature. The mixture was filtered through a pad of kieselguhr and the solvent was removed by evaporation to give a solid residue which was crystallised from ethyl acetate/hexane to give 3,4-di-t-butoxycarbonylmethoxybenzoic acid; m.p. 118°-120° C.; NMR Spectrum (d6 -DMSO) 1.41 (s, 18H), 4.7 (s, 2H), 4.76 (s, 2H), 6.95 (d, 1H), 7.39 (m, 1H), 7.55 (dd, 1H); Microanalysis found: C, 59.5; H, 6.8%; C19H26O8 requires C, 59.7; H, 6.9%.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH:5]1([NH:11][N:12]=[CH:13][C:14](=[O:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O>[OH:16][C:14]1[C:13]([C:1](=[O:2])[CH3:3])=[N:12][N:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:15]=1
Reactant: O=CC=O
Reactant: CC(=O)C=NNC1CCCCC1
Solvent: O
Product: CC(=O)c1nn(C2CCCCC2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
A 40% aqueous solution of glyoxal (1.73 mL, 15.1 mmol) was added to 2-oxopropanal cyclohexyl-hydrazone (2.54 g, 15.1 mmol) in H2O (125 mL). The mixture was then heated at reflux. After 1 hour, the mixture was cooled to room temperature and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 3.22 g of 1-(4-hydroxy-1-cyclohexyl-1H-pyrazol-3-yl)ethanone as a yellow oil. The crude product was then used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[CH3:41][NH:42][C:43](=[O:46])[CH2:44][NH2:45]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:37])([CH3:38])[CH2:9][C:10]([OH:36])([C:32]([F:34])([F:35])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([NH:45][CH2:44][C:43]([NH:42][CH3:41])=[O:46])=[O:27])[CH:7]=1
Reactant: CNC(=O)CN
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Product: CNC(=O)CNC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and N1-methylglycinamide with System A used for purification by mass directed autopreparation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:3]=1
Reactant: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1
Reactant: OB(O)c1cncnc1
Product: COc1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1
Yield: 59 %

Procedure:
The title compound was synthesized as described for Example 1 in 59% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(4-methoxyphenyl)-1H-isoindol-3-amine (0.13 g, 0.25 mmol) and 5-pyrimidinylboronic acid (0.037 g, 0.30 mmol):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:16])=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[K+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:17])[CH:3]=1)[NH:16][C:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:8]2
Reactant: Nc1c(F)cc(Cl)cc1C#Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1cc(Cl)cc2cc(-c3cccnc3)[nH]c12
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine (3.1 g, 12.57 mmol) in NMP (40 mL) is added potassium tert-butoxide (2.1 g, 18.85 mmol) and the mixture is stirred overnight. Water (1 mL) is added to quench the reaction and the mixture is poured into water (100 mL). The mixture is extracted with diethyl ether five times. The combined organic phase is partially concentrated, resulting in precipitation of the product, which is filtered through a glass sintered funnel and washed with dichloromethane to afford 5-chloro-7-fluoro-2-pyridin-3-yl-1H-indole as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.15 (m, 2H), 7.47-7.53 (m, 2H), 8.31 (dt, J=8.2, 1.9, 1.8 Hz, 1H), 8.55 (d, J=4.3 Hz, 1H), 9.16 (s, 1H), 12.23 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:46][C:47]1[C:48]([C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:49][C:50]([C:54]([CH3:57])([CH3:56])[CH3:55])=[C:51]([OH:53])[CH:52]=1>CN(C=O)C.CCOCC.CCO>[OH:53][C:51]1[C:50]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][C:48]([C:58]([CH3:60])([CH3:59])[CH3:61])=[C:47]([NH:46][C:12]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=2)=[O:14])[CH:52]=1
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3ccccc3c2=O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65° C.) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et2O was added to the material obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25° C.) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide 8 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white powdery solid (38 g, 52%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.[CH:10]1([CH:13](O)[C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[NH:18][CH2:17]3)[CH2:12][CH2:11]1>O1CCOCC1>[CH:10]1([CH:13]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[NH:18][CH2:17]3)[CH2:11][CH2:12]1
Reactant: O=C1NCc2cc(C(O)C3CC3)ccc2N1
Reactant: c1nc[nH]n1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=C1NCc2cc(C(C3CC3)n3cncn3)ccc2N1
Yield: 1.7 %

Procedure:
To a stirred and cooled (15° C.) solution of 2.5 parts of 1H-1,2,4-triazole in 70 parts of 1,4-dioxane was added dropwise 1 part of thionyl chloride under nitrogen atmosphere. After stirring for 10 minutes at 20° C., a solution of 2 parts of 6-(cyclopropylhydroxymethyl)-3,4-dihydro-2(1H)-quinazolinone in 80 parts of 1,4-dioxane was added portionwise to the previous mixture at 20°-25° C. After stirring overnight at room temperature, the precipitated product was filtered off, washed with 1,4-dioxane and purified by column chromatography over silica gel using a mixture of dichloromethane, methanol and methanol, saturated with ammonia (90:5:5 by volume) as eluent. The eluent of the desired fraction was evaporated and the residue was further purified, first by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (96:4 and 97.5:2.5 by volume) and then by column chromatography (RP 18) using a mixture of water and methanol (80:20 by volume) as eluents. The eluent of the desired fraction was evaporated and the residue was stirred in 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 0.04 parts (1.7%) of 6-[cyclopropyl(1H-1,2-4-triazol-1-yl)methyl]-3,4-dihydro-2(1H)-quinazolinone; mp. 184.4° C. (comp. 25).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:50].[K+].Cl>O1CCOCC1.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:50])[C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2cc(OCc3ccccc3)cc(O)c2s1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
5-(benzyloxy)-7-bromo-2-methylbenzo[d]thiazole 4.03D (560 mg, 1.7 mmol) Pd2(dba)3 (77 mg, 0.084 mmol), and 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (142 mg, 0.335 mmol) were taken up in 1,4-dioxane (6 mL) under Ar. Aqueous 2 M KOH (2.5 mL, 5 mmol) was added and the mixture was heated to 90° C. After 1 h, the mixture was cooled to r.t. and was diluted with EtOAc (50 mL), and water (30 mL). The aqueous phase was and acidified with 3 M aqueous HCl (1.8 mL, 5.4 mmol). The phases were separated, and the organic phase was washed with saturated aqueous NaHCO3 (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (10-55% EtOAc in hexanes) to provide 5-(benzyloxy)-2-methylbenzo[d]thiazol-7-ol 4.03E. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H14NO2S: 272.1; found 272.1.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@@H:35]([CH3:45])[CH2:36][CH2:37][NH:38][CH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1.C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:4])[N:34]4[C@@H:35]([CH3:45])[CH2:36][CH2:37][N:38]([CH:39]5[CH2:44][CH2:43][S:42][CH2:41][CH2:40]5)[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: C[C@H](N)CCNC1CCSCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1CCN(C2CCSCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 49.2 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (25 mg, 0.055 mmol) and free based [(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine (48 mg, 0.26 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (16 mg, 49%) as a film. This material was debenzylated in a second step in a manner similar to Z-26 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (8 mg, 59%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J=7.2 Hz, 3H), 1.53-1.58 (m, 1H), 1.72-2.10 (m, 5H), 2.56-2.76 (m, 5H), 2.84-2.87 (m, 2H), 4.18 (dd, J=2.8, 14.0 Hz, 1H), 4.26 (dd, J=3.4, 14.2 Hz, 1H), 4.92-4.97 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.36 (m, 2H), 8.31 (s, 1H), 10.48 (m, 1H), 12.48 (br, 1H); ES+ MS: 501 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([OH:25])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]N(C)P(N(C)C)(N(C)C)=O.CI>C1COCC1.OS([O-])(=O)=O.[Na+]>[CH:1]1([CH2:7][C:8]2([O:25][CH3:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(N2CCC(O)(CC3CCCCC3)CC2)cc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(CC3CCCCC3)(OC)CC2)cc1
Temperature: 50 °C

Procedure:
A solution of Example 1F (380 mg) in THF (5 mL) was treated with NaH (96 mg, 60% dispersion in mineral oil), heated to 50° C. for 2 hours, and treated with hexamethylphosphoramide (1 mL) followed by MeI (1 mL). The reaction mixture was refluxed overnight, cooled to 0° C., and diluted with saturated aqueous NaHSO4 solution (10 mL). The resulting two-phase mixture was separated, the aqueous phase was extracted twice with ether, and the combined organic layers washed with water and brine. After drying over MgSO4, the mixture was concentrated in vacuo and purified by silica gel chromatography eluting with 15% ethyl acetate in hexanes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>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(=O)([O-])[O-].[Na+].[Na+]>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: CCCCCCCCC1COC(c2ccc(Br)cc2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCC1COC(c2ccc(-c3cccc(F)c3F)cc2)OC1

Procedure:
Quantities: compound from Example 14 (10.7 g, 30 mmol), compound from Example 36 (5.5 g, 35 mmol), tetrakis(triphenylphosphine)palladium(0) (1.04 mg, 0.9 mmol) and aqueous sodium carbonate (30 cm3, 2M). The experimental procedure was as described in Example 63.