Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:8]([OH:24])=[C:9]([C:21](=[O:23])[CH3:22])[CH:10]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]([C:9]1[C:8]2[O:24][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
21.0 mL (258 mmol) chloroacetyl chloride are added dropwise to 60.0 g (233 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone and 70.0 g (506 mmol) potassium carbonate while being cooled with the ice bath. Then the mixture is stirred overnight at ambient temperature and then for 6 hours at reflux temperature. The hot reaction mixture is filtered, then evaporated down to approx. 400 mL and combined with ice water. The precipitate obtained is suction filtered, dried and purified by chromatography on a short silica gel column (dichloromethane:methanol=99:1). The fractions containing the product are evaporated down, suspended in isopropanol/diisopropylether, suction filtered and washed with diisopropylether. Yield: 34.6 g (50%); mass spectroscopy [M+H]+=298.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[CH2:10]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]Br)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14].[Mg].[Cl-].[NH4+]>C(OCC)C>[CH2:10]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: N#CC1CCC(=O)CC1
Reactant: CCCCCc1ccc(CCBr)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCc1ccc(CC[C@H]2CC[C@H](C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 6 g of 4-cyanocyclohexanone in 50 ml of diethyl ether is added dropwise, while stirring, at room temperature and during the course of 1.5 hours, to a Grignard solution prepared from 13 g of 1-(4-n-pentylphenyl)-2-bromoethane and 1.3 g of magnesium turnings in 200 ml of diethyl ether. The reaction mixture is then heated under reflux to the boil for 2 hours, and, after it has cooled, 150 ml of 10% aqueous ammonium chloride solution is added to it, while stirring. The ether phase is separated off, dried over sodium sulfate and evaporated. The residual 1-(4-n-pentylphenyl)-2-(4-cyano-1-hydroxycyclohex-1-yl)-ethane is dissolved in 40 ml of acetone and this solution is heated to the boil for 1 hour with 0.5 g of p-toluenesulfonic acid. The solvent is then distilled off and the residue is taken up in 100 ml of ethanol. After the addition of 20 mg of copper (II) sulfate, 23 g of hydrazine hydrate and 40 ml of 30% aqueous hydrogen peroxide solution are added successively to the mixture at 0°. The reaction mixture is stirred for 1 hour at room temperature and poured into 500 ml of water, and the 1-(4-n-pentylphenyl)-2-(trans-4-cyanocyclohexyl)-ethane thus obtained is extracted with diethyl ether; the extracts are dried with sodium sulfate and evaporated, and the residue is recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=[CH:30]C=CC=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=CC(F)=C(N)C=2)C=CN=1.C1(S(Cl)(=O)=O)CC1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([CH:26]3[CH2:31][CH2:30]3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)C1CC1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine (283 mg, 0.811 mmol) and cyclopropanesulfonyl chloride (114 mg, 0.811 mmol) the title compound was obtained as a white solid (247 mg, 67% yield). MS (ESI): 453.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([S:13](Cl)(=[O:15])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]([NH:38]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]3)=[O:30])[S:26][C:22]=2[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]([NH:38][S:13]([N:9]3[CH2:8][CH2:7][C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:10]3)(=[O:15])=[O:14])[C:29]([N:31]3[CH2:32][CH2:33][CH:34]([CH3:37])[CH2:35][CH2:36]3)=[O:30])[S:26][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Product: COc1ccc2c(c1)CN(S(=O)(=O)NC(Cc1cc3c(N)nccc3s1)C(=O)N1CCC(C)CC1)CC2

Procedure:
This compound was prepared from 200 mg of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 110 mg; m.p. 175-1 76° C., (+)-FAB-MS: 544 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[CH:20]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:22][CH:23]1[CH2:36][C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[N:33]=3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:38][O:37][C:32]1[N:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][C:26]1[O:25][CH2:24][CH:23]([CH2:22][N:1]3[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]4[CH:11]=[CH:12][C:13]5[S:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=5[CH:20]=4)=[O:9])[CH2:3][CH2:2]3)[CH2:36][C:35]2=1
Reactant: COc1ccc2ncc3c(c2n1)CC(CBr)CO3
Reactant: O=C1CSc2ccc(C(=O)NC3CCNCC3)cc2N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc3c(c2n1)CC(CN1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 80 °C
Reaction time: 24 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid piperidin-4-ylamide (56 mg, 0.16 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-oxa-5,9-diaza-phenanthrene (50 mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by N,N-diisopropylethylamine (30 μL, 0.17 mmol, 1.1 eq). After 24 hours stirring at 80° C., solvent is removed and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(6-methoxy-3,4-dihydro-2H-1-oxa-5,9-diaza-phenanthren-3-ylmethyl)-piperidin-4-yl]-amide as an off-white lyophilized powder (39 mg, 47% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][CH2:10][CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].Cl.O1CCOC[CH2:14]1>CO>[NH2:2][C@@H:3]([CH2:9][CH2:10][CH3:11])[C@@H:4]([OH:8])[C:5]([O:7][CH3:14])=[O:6].[NH2:2][C@@H:3]([CH2:9][CH2:10][CH3:11])[C@H:4]([OH:8])[C:5]([O:7][CH3:14])=[O:6]
Reactant: CCC[C@H](N)C(O)C(=O)O
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: CCC[C@H](N)[C@@H](O)C(=O)OC
Product: CCC[C@H](N)[C@H](O)C(=O)OC
Reaction time: 8 h

Procedure:
To a solution of 1 g of (3S)-3-amino-2-hydroxyhexanoic acid hydrochloride in 10 mL of methanol was added 10 mL of a 4 M hydrogen chloride/dioxane solution, followed by stirring overnight, and the solvent was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 425 mg of methyl (2R,3S)-3-amino-2-hydroxyhexanoate and 130 mg of methyl (2S,3S)-3-amino-2-hydroxyhexanoate.
Reaction SMILES: [I:1]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[C:27]([O:35][C@H:36]1[C:40]([F:42])([F:41])[CH:39](O)[O:38][C@@H:37]1[CH2:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.CCCCCC>[C:27]([O:35][C@H:36]1[C:40]([F:42])([F:41])[CH:39]([I:1])[O:38][C@@H:37]1[CH2:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: O=C(O[C@@H]1[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(O)C1(F)F)c1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(O[C@@H]1[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(I)C1(F)F)c1ccccc1
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
I2 (0.524 g) and dichloromethane (8 mL) were charged into a round bottom flask in the dark. To this solution was added dropwise a solution of Ph3P (0.634 g) in dichloromethane (8 mL) at ambient temperature. The resulting suspension was stirred at this temperature for 30 minutes and imidazole (0.734 g) was added. After the resulting suspension was stirred for 5 minutes at room temperature, a solution of lactol 8 (0.8 g) in dichloromethane (8 mL) was added dropwise and the resulting solution was stirred overnight at room temperature. Hexane (30 mL) was added and then the suspension was stirred for 10 minutes, filtered, and concentrated to give 1.1 g of (2R,3R)-4,4-difluoro-5-iodo-2-(trityloxymethyl)tetrahydrofuran-3-yl benzoate 10.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:30](=[O:32])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: CNC
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: CN(C)C(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 73 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with dimethylamine to give the title compound as a white solid (183 mg, 73%); NMR Spectrum 2.97 (s, 3H), 3.04 (s, 3H), 5.17 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.22 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.76-7.69 (m, 3H), 7.91 (m, 1H), 8.15 (s, 1H), 8.53 (m, 2H), 8.57 (s, 1H), 11.21 (br s, 1H); Mass spectrum MH+ 454.
Reaction SMILES: CC([O:4][C@@H:5]1[C@@:9]2([CH3:24])[CH2:10][CH2:11][C@@H:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:23])=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][C@H:13]3[C@@H:8]2[CH2:7][CH2:6]1)=O.CO.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[CH3:24][C@@:9]12[C@@H:5]([OH:4])[CH2:6][CH2:7][C@H:8]1[C@H:13]1[C@@H:12]([C:21]3[CH:20]=[C:19]([OH:22])[C:18]([OH:23])=[CH:17][C:16]=3[CH2:15][CH2:14]1)[CH2:11][CH2:10]2
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(O)cc4[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4cc(O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
To the crude product (100 g) of 2-hydroxyestradiol 17-acetate obtained by the process described in Example 3-a, MeOH (3600 ml) and concentrated HCl (400 ml) were added, and the solution was refluxed for 1 hour. After the reaction mixture was cooled, water and AcOEt were added to it and the solution was neutralized by addition of NaHCO3, and extracted with AcOEt. The organic layer was washed with brine, and dried over anhydrous Na2SO4, and then evaporated in vacuo to obtain a crude product (68.7 g), which was, in turn, subjected to silica gel chromatography (elution solvent, hexane:AcOEt=1:1) to afford 59 g (91% from 2-acetylestradiol 17-acetate) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[Br-].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Zn+].CCCCCC>C1COCC1.CCOC(C)=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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Br)ccc1-c1ccccn1
Temperature: 70 °C
Yield: 47.8 %

Procedure:
1-Bromo-3-fluoro-4-iodo benzene (5.0 g, 16.6 mmol), 2-pyridylzinc bromide (7.4 g, 33.2 mmol) were combined in dry THF (100 mL) under argon and Pd(PPh3)4 (1.9 g, 1.6 mmol) was added. The reaction mixture was heated at 70° C. overnight. The reaction mixture was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (300 mL), and washed with H2O (3×100 mL), brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil. The crude product was purified by column chromatography eluting with 1:9 EtOAc:Hexane to afford 2-(4-bromo-2-fluorophenyl)pyridine (2.0 g, 50% yield) as a yellow solid. MS 254.1 (M++H).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:15]2[N:23]3[C@@H:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:25][O:26][C:21]4=[C:22]3[C:17](=[CH:18][CH:19]=[C:20]4[C:33]3[C:34]([CH3:39])=[N:35][O:36][C:37]=3[CH3:38])[N:16]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.CO>[CH3:39][C:34]1[C:33]([C:20]2[C:21]3[O:26][CH2:25][C@H:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[N:23]4[C:15]([N:8]5[CH2:14][CH2:13][CH2:12][N:11]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:10][CH2:9]5)=[N:16][C:17]([C:22]=34)=[CH:18][CH:19]=2)=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1-c1ccc2nc(N3CCCN(S(C)(=O)=O)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
Triethylamine (8.1 μL, 0.058 mmol) was added to a solution of (4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (5.0 mg, 0.012 mmol) in methylene chloride (0.44 mL), and the mixture was cooled to 0° C. Methanesulfonyl chloride (1.8 μL, 0.023 mmol) was then added and the mixture was stirred for 5 min at 0° C. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (3.8 mg, 64%). LCMS calc. for C25H29N6O4S (M+H)+: m/z=509.2. found: 509.2.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH:33]([CH3:35])[CH3:34])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1.[H][H].CO>C(O)C.ClCCl.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:28][CH2:29][N:30]([CH:33]([CH3:35])[CH3:34])[C:31](=[O:32])[C:10]=12
Reactant: CC(C)N1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 64.1 %

Procedure:
To a stirred solution of 9-benzyloxy-2-isopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (440) (50 mg, 0.106 mmol) in ethanol (5 mL), Pd—C (10% w/w, 10 mg) was added and the reaction mixture was allowed to stir for 1 h in a hydrogen atmosphere at balloon pressure while silica thin layer chromatography was performed (10% methanol in dichloromethane; Rf=0.3). After completion of the reaction, the reaction mixture was filtered through a celite bed and concentrated to obtain a crude product which was purified by normal silica gel (100-200 mesh) column chromatography using 2-5% methanol in dichloromethane as a gradient polarity mobile phase to get 9-hydroxy-2-isopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (441) (26 mg, 64%) as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:36][C:33]1[CH:32]=[N:31][C:30]([N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH2:25][CH2:26]2)=[N:35][CH:34]=1
Reactant: CS(=O)(=O)OCC1CCN(c2ncc(F)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnc(OCC3CCN(c4ncc(F)cn4)CC3)cn2)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 0.15 g, 0.60 mmol), [1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]methyl methanesulfonate (0.234 g, 0.81 mmol) and K2CO3 (0.17 g, 1.20 mmol) in DMF (6 mL) was stirred at 100° C. in a preheated oil bath for 2.5 h. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude product as a light brown solid. The crude product was purified by chromatography on a silica gel column eluted with 1:30 acetone/CH2Cl2 then 1:20 acetone/CH2Cl2 to give 0.132 g (50%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.30 (s, 1H), 8.18 (s, 2H), 8.11 (d, 2H, J=8.0 Hz), 8.02 (d, 2H, J=8.1 Hz), 4.80-4.65 (m, 2H), 4.25 (d, 2H, J=6.6 Hz), 3.07 (s, 3H), 3.00-2.85 (m, 2H), 2.10-2.05 (m, 1H), 2.00-1.85 (m, 2H), 1.45-1.30 (m, 2H); LRMS (ESI), m/z 444 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:37]([O:54][CH2:55][CH2:56]/[C:57](=[N:59]/O)/[NH2:58])([C:50]([CH3:53])([CH3:52])[CH3:51])([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[Si:37]([O:54][CH2:55][CH2:56][C:57]1[N:59]=[C:6]([C:5]2[C:4]([CH3:11])=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[O:8][N:58]=1)([C:50]([CH3:53])([CH3:51])[CH3:52])([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)[Si](OCC/C(N)=N/O)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: N#CC(Cl)(Cl)Cl
Product: Cc1nc(Cl)ccc1-c1nc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)no1
Temperature: 100 °C

Procedure:
6-Chloro-2-methylnicotinic acid (Example 425, Step 1) (150 mg, 0.87 mmol) trichloroacetonitrile (0.13 ml, 1.31 mmol) and solid supported triphenylphosphine on polystyrene (1.88 mmol/g, 1.5 g, 2.62 mmol) were taken up in tetrahydrofuran (10.9 ml). The mixture was heated in the microwave at 100° C. for 5 minutes and cooled to room temperature. (1Z)-3-{[tert-Butyl(diphenyl)silyl]oxy}-N′-hydroxypropanimidamide (329 mg, 0.96 mmol), THF (5 mL), and N-ethyl-N-isopropylpropan-2-amine (0.15 ml, 0.87 mmol) were added. The resulting mixture was heated in the microwave at 150° C. for 15 minutes, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified via silica gel chromatography (0-35% ethyl acetate in hexane) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[OH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C=CC(=O)Oc2ccc(C(=O)O)cc2)cc1
Reaction time: 1 h

Procedure:
This step illustrates the addition of an aryl group to the compound of Step 2 to increase the stiffness and rod-like characteristics of the alkyl or alkoxy substituted cinnamoyl group. The compound of Step 2 (1.0 gm=5.1 mmole) was slurried under N2 in 10 mL dry pyridine. N,N-diisopropylethylamine (0.7 gm=5.6 mmole) was added, followed by a spatula tip of 4-dimethylaminopyridine. A solution of p-hydroxybenzoic acid (0.7 gm, 5.1 mmole) in 7 mL pyridine was added dropwise to the above slurry. An amber-orange solution soon developed. The solution was stirred for 60 minutes after addition was complete, and it was dropped slowly into 200 ml ice/H2O containing 25 mL concentrated HCl. The resulting precipitate was collected by suction filtration, slurried twice with H2O on the funnel, and dried in a 40° C. vacuum oven. The white solid was recrystallized from boiling acetone. White needles, K280° l.c. Yield 0.6 gm. Elemental Analysis: C17H14O 5, mol. wt. 298.3. Calcd: C, 68.5, H, 4.7, O, 26.8. Found: C, 68.5, H, 4.7. 1H NMR (DMSO-d6): δ (ppm) 6.7 (1H, d), 8.0 (1H, d).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: OB(O)c1cccc(Cl)c1
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+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(Cl)c3)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (3-chlorophenyl)boronic acid (0.072 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonate in water (0.5 mL, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-30% ethyl acetate/hexanes) to give the desired product. LCMS calculated for C15H13ClN5OS (M+H)+: m/z=346.1. Found: 346.0.