Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[CH2:12][CH2:11][C:10](=[O:29])[N:9]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:30]([N:9]1[C:10](=[O:29])[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:14](=[O:15])[N:8]1[CH2:7][C:6]([OH:37])=[O:5])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1

Procedure:
{2-Benzyl-6-[(isoquinoline-1-carbonyl)-amino]-3,7-dioxo-[1,2]diazepan-1-yl}-acetic acid tert-butyl ester (7a) (115 mg, 0.23 mmol) was stirred in 20% of trifluoroacetic acid (TFA) in dichloromethane (2 mL) overnight. The solution was evaporated to afford {2-benzyl-6-[(isoquinoline-1-carbonyl)-amino]-3,7-dioxo-[1,2]diazepan-1-yl}-acetic acid (8a). 1H-NMR (500 MHz, CDCl3) δ 2.05-2.11 (m, 1H), 2,45-2.50 (m, 1H), 2.72-2.83 (m, 1H), 3.45-3.54 (m, 1H), 4.01-4.06 (d, 1H), 4.59-4.63 (d, 1H), 4.70-4.82 (m, 2H), 4.93-4.98 (d, 1H), 7.28-7.42 (m, 5H), 7.80-8.10 (m, 4H), 8.40-8.52 (m, 2H), 8.85 (d, 1H). The acid (8a) was dissolved in dichloromethane (2 mL) followed by addition of HOBT (77 mg, 0.57 mmol) and EDC (110 mg, 0.57 mmol) and stirred for 30 min. A solution of (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (9, anti diastereomer) (166 mg, 0.57 mmol) in dichloromethane/DMF (3/1 mL), charged with 1,3-dimethylbarbituric acid (DMBA) (90 mg, 0.57 mmol) and Pd(PPh3)4 (66 mg, 0.057 mmol) for 30 min, was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×3), dried over Na2SO4, filtered and evaporated to give a pale yellow solid, that was purified by flash chromatography using dichloromethane/methanol (99.5/0.5 to 98.5/1.5) to afford 97.5 mg (67% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 2.03-2.13 (m, 1H), 2.40-2.43 (d, 1H), 2.55-2.60 (m, 1H), 2.83-2.92 (m, 1H), 3.04-3.10 (q, 1H), 3.28-3.38 (m, 1H), 4.08-4.11 (d, 1H), 4.20-4.24 (d, 1H), 4.38-4.41 (m, 1H), 4.67-4.70 (d, 1H), 4.78-4.87 (m, 2H), 4.91-5.02 (m, 2H), 5.36 (s, 1H), 6.05 (d, 1H), 7.20-7.38 (m, 10H), 7.68-7.78 (m, 2H), 7.80-7.88 (m, 2H), 8.48 (d, 1H), 8.70 (d, 1H), 9.49 (d, 1H). Analytical HPLC: 12.53 min. LC-MS (ES+): m/e=636 (M+H+).
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].P(Cl)(Cl)([Cl:14])=O>[Cl-].C[N+](CC)(CC)CC.C(#N)C>[NH2:3][C:2]1[N:4]=[C:5]2[C:9]([NH:8][CH:7]=[N:6]2)=[C:10]([Cl:14])[N:1]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](C)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 58.1 %

Procedure:
A mixture of guanine (22.7 g, 0.15 mol), methyltriethylammonium chloride (TEMAC) (45.5 g, 0.3 mol), phosphorus oxychloride (82.6 ml, 0.9 mol) and acetonitrile (67 ml) was heated at 60° C. with stirring for 6 hours and then cooled to 10° C. The solid material was filtered off and suspended in water (300 mls). The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide to achieve dissolution and powdered carbon (6.8 g) added. The mixture was stirred for 1 hour and then filtered to remove the carbon. Acetone (72 mls) was added and then the pH reduced to 7 with dilute hydrochloric acid. The product was filtered off, washed with acetone/water (50:50 mixture, 50 mls), water (50 mls), acetone/water (50:50 mixture, 50 mls) and acetone (50 mls) and then dried to give 2-amino-6-chloropurine as a cream coloured solid (14.77 g, 54% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][C:16]([CH3:20])=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1nc(Br)ccc1C(=O)O
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)nc1C
Yield: 57.6 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (745 mg) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (744 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (801 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:12][CH2:11][C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: CC(C)(C)c1ccc(CN)cc1
Product: CC(C)(C)c1ccc(CNC(=O)c2cn3cc(Br)ccc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-(tert-butyl)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials. 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 7.88 (d, 1H), 7.79 (d, 1H), 7.36 (d, 2H), 7.32 (d, 2H), 4.60 (d, 2H), 1.38 (s, 9H). MS 385.9, 387.9 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[N:12]=[C:11]3[S:13][C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])=[N:15][C:10]3=[CH:9][CH:8]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C.O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[S:13][C:11]3[C:10]([N:15]=2)=[CH:9][CH:8]=[C:7]([O:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]4[C:33](=[O:42])[N:32]([C:29]5[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=5)[C:37]([CH3:38])=[CH:36][CH:35]=4)=[O:40])=[CH:3][C:4]=2[F:24])[N:12]=3)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
N-[5-(4-Amino-2-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (240 mg, 0.70 mmol), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (190 mg, 0.77 mmol) and HATU (340 mg, 0.91 mmol) were suspended in N,N′-dimethylformamide (3.0 mL), and N,N-diisopropylethylamine (0.24 mL, 1.4 mmol) was added. After stirring at room temperature for 8 hr, the mixture was diluted with ethyl acetate (5.0 mL) and tetrahydrofuran (5.0 mL). The mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The resulting precipitate was collected by filtration to give the title compound (350 mg, 0.61 mmol, 88%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:36][CH:33]([CH3:35])[CH3:34])[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: CC(C)NCCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.378 g, 0.800 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. Additional isopropyl amine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 10% methanol in chloroform. After drying in vacuo at 80° C. for 30 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-isopropyl-amine as a pale yellow solid was obtained (0.110 g, 38.2%). This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 74° C. for 13.5 hours to yield the hydrochloride as an off-white solid (0.117 g): MP: 275-7° C. (dec); Mass Spectrum (+EI, [M+H]+) m/z 360. 1HNMR (500 MHz, DMSO-d6): δ14.22 (br, 1H), 8.75 (br, 2H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1H, J=2.08 Hz), 7.19 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.30-4.33 (m, 2H), 3.34-3.40 (m, 3H), 1.25 ppm (d, 6H, J=6.59 Hz). Elemental Analysis for C18H21N3O3S.1.00 mol HCl.0.10 mol H2O: Calcd: C, 54.36; H, 5.36; N, 10.57; Found: C, 54.02; H, 5.42; N, 10.22.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:6][CH:5]([NH:7]C(=O)OC(C)(C)C)[CH:4]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)[CH2:3]1.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:7][CH:5]1[CH2:6][C:2]([F:29])([F:1])[CH2:3][CH:4]1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[N:24]=[CH:25][CH:26]=[N:27]1
Reactant: CC(C)(C)OC(=O)NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl N-{4,4-difluoro-2-[2-(2H-1,2,3-triazol-2-yl)benzamido]cyclopentyl}carbamate (640 mg, 1.57 mmol) in dry 1,4-dioxane (5 ml) was added HCl in 1,4-dioxane (4M, 3.9 ml, 15.71 mmol). The reaction was stirred at room temperature for 6 hours then concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:55])([CH3:54])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:53])([C@@:17]4([CH3:52])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[C:48]([O:47][C:45]([N:42]1[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][NH:36][C@:20]23[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]2[C@@H:22]2[C@@:17]([CH3:52])([CH2:18][CH2:19]3)[C@@:16]3([CH3:53])[C@@H:25]([C@:26]4([CH3:29])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:55])([CH3:54])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)=[CH:28][CH2:27]4)[CH2:24][CH2:23]2)[CH2:44][CH2:43]1)=[O:46])([CH3:49])([CH3:50])[CH3:51]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 80 °C
Yield: 40.8 %

Procedure:
A mixture of tert-butyl 4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)piperazine-1-carboxylate (4 mg, 5.29 μmol) and sodium hydroxide (0.053 mL, 0.053 mmol) in dioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixture was filtered and the clear solution was purified by HPLC to provide the desired product as white solid (1.6 mg, 39%). LCMS: m/e 742.65 (M−H)−, 2.68 min (method 10). 1H NMR (500 MHz, Acetic) δ 8.03 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.75 (s, 1H), 3.73 (br. s., 4H), 3.66-3.45 (m, 4H), 3.21 (br. s., 4H), 2.98-2.75 (m, 1H), 2.31-1.00 (m, 22H), 1.77 (s, 3H), 1.50 (s, 9H), 1.23 (s, 3H), 1.13 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:24])(=[O:11])=[O:10])=[O:7])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[Cl:24][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10]
Reactant: CCCCNC(=O)NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: O=C=NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 9.5 g (0.026 mol) of N-(butylaminocarbonyl)-2-chloro-6-phenylbenzenesulfonamide of Example 3 and 0.02 g DABCO was heated in 120 ml dry xylenes to reflux (138°) with a short water condenser and dry ice cold finger condenser attached. An excess of phosgene gas was introduced and reflux was continued for 2 hours. The mixture was then cooled, filtered under nitrogen atmosphere then evaporated to an amber oil, 8.5 g. An infrared spectrum exhibited an absorption at 2250 cm-1 indicating the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]([O:15]CC)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: CCOC(=O)COc1cccc2cccnc12
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COc1cccc2cccnc12)NC[C@@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a stirred mixture of ethyl 2-(quinolin-8-yloxy)acetate (250 mg, 1.08 mmol) in EtOH (2 mL) was added (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (222 mg, 1.08 mmol). The mixture was stirred at 120° C. for 0.5 hour under microwave heating. After evaporation of the solvent, the residue was purified first by prep-TLC and then by prep-SFC to afford (160 mg Yield 40%). 1H NMR (400 MHz, MeOD) δ=8.791 (d, J=4.3 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 7.51-7.46 (m, 3H), 7.17 (d, J=7.3 Hz, 1H), 6.94-6.85 (m, 4H), 4.65 (s, 2H), 4.00-3.99 (m, 1H), 3.59 (s, 2H), 3.44-3.32 (m, 2H), 2.77-2.71 (m, 4H), 2.53-2.51 (m, 2H). LCMS (m/z): 392.1 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[SH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
2-Fluoro-5-nitrobenzaldehyde (0.16 g, 0.95 mmol) was dissolved in N,N-dimethylformamide (8.1 mL), and 4-mercaptophenol (0.11 g, 0.86 mmol) and triethylamine (0.27 mL, 1.9 mmol) were added thereto, followed by stirring at 25° C. for 1 hour. After the conventional treatment, the product was purified by silica gel column chromatography (eluted by n-hexane/acetone=4/1-1/1) to give 5-nitro-2-[(4-hydroxyphenyl)thio]benzaldehyde (0.18 g, 70%).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+].CCOCC.O>[CH2:19]([O:18][CH2:17][CH2:16][CH2:15][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCCC1
Reactant: BrCCCOCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=C1CCCCC1CCCOCc1ccccc1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
Example 234 A) To a mechanically stirred mixture of KOt-Bu (10.1 g, 104 mmol) in benzene (100 mL) cooled to 0° C. under nitrogen was added cyclohexanone (7.4 g, 83 mmol) dropwise over 20 min. Ten minutes after the addition was complete, benzyl 3-bromo-propyl ether (20 g, 87 mmol) was added over a twenty minute period. The reaction mixture was warmed to room temperature, refluxed for seven hours, stirred at room temperature or eighteen hours, and diluted with 0.5N potassium hydrogen sulfate (200 mL). The reaction mixture was further diluted with Et2O, 0.5N potassium hydrogen sulfate, and water, until two phases formed. The organic phase was washed with water, brine, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give 19.2 g of the 2-(3-benzyloxypropyl)-cyclohexan-1-one.
Reaction SMILES: FC1C=CC2OC(CCC)CC(=O)C=2C=1.C([O:23][N:24]1[CH2:28][CH2:27][C:26]2([C:33]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=3[O:31][CH:30]([CH:39]([CH3:41])[CH3:40])[CH2:29]2)[C:25]1=[O:42])C1C=CC=CC=1.C1(CCC2OC3C=CC=CC=3C(=O)C=2)C=CC=CC=1>>[OH:23][N:24]1[CH2:28][CH2:27][C:26]2([C:33]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=3[O:31][CH:30]([CH:39]([CH3:40])[CH3:41])[CH2:29]2)[C:25]1=[O:42]
Reactant: CC(C)C1CC2(CCN(OCc3ccccc3)C2=O)c2cc(F)ccc2O1
Agent: CCCC1CC(=O)c2cc(F)ccc2O1
Agent: O=c1cc(CCc2ccccc2)oc2ccccc12
Product: CC(C)C1CC2(CCN(O)C2=O)c2cc(F)ccc2O1

Procedure:
Prepared from 2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one via the intermediacy of the more polar diastereomer of 1'-benzyloxy-2,3-dihydro-6-fluoro-2-(2-propyl)-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one (Rf=0.2, 1:1 diethyl ether/hexanes) using the same procedure for preparation of Example 7 from 2,3-dihydro-6-fluoro-2-(2-phenylethyl-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[CH3:33][O:34][C:35]1[N:36]=[CH:37][C:38]([C:41](O)=[O:42])=[N:39][CH:40]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>ClCCl.CN(C)C=O.O>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:4]2[CH:3]=[C:2]([NH:1][C:41]([C:38]3[CH:37]=[N:36][C:35]([O:34][CH3:33])=[CH:40][N:39]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Reactant: COc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(C(=O)Nc2cccc([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
N-[(4aR,7aS)-7a-(3-Aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (400 mg, 891.81 μmole) and 5-methoxypyrazine-2-carboxylic acid (165 mg, 1.07 mmol) are combined in dichloromethane (4 mL) and dimethylformamide (0.5 mL). 1-Hydroxybenzotriazole (160 mg, 1.16 mmol) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (226 mg, 1.16 mmol) are added and the resulting mixture is stirred for 5 hours at room temperature under nitrogen. The reaction mixture is diluted with water and the pH is adjusted to ˜12 with 1 N NaOH. The mixture is extracted with ethyl acetate (3×). The combined organic extracts are dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 20 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (482 mg, 92%). ES/MS (m/e): 585 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:23]1(=O)[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1)=[O:5]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC1CCCC1
Reactant: O=C1CCCC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1OCC1CCCC1

Procedure:
0.550 g (1.60 mmol) of 2-chloro-3-cyclopentylmethoxy-4-ethylsulfonylbenzoic acid, 0.196 g (1.70 mmol) of cyclohexane-1,3-dione, 0.279 g (1.40 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.002 g of dimethylaminopyridine were stirred for 10 hours at room temperature in 15 ml of methylene chloride. The mixture was subsequently diluted with methylene chloride and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. After the combined organic phases had been dried over Na2SO4 and evaporated completely on a rotary evaporator, 3-oxo-1-cyclohexenyl 2-chloro-3-cyclopentylmethoxy-4-ethylsulfonylbenzoate was obtained in the form of a brown resin.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:9][CH:8]=[C:7]([CH:10]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][C:12]#[N:13])[CH:6]=1)C.C1COCC1.Cl>O>[CH:4]([C:5]1[S:9][CH:8]=[C:7]([CH:10]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][C:12]#[N:13])[CH:6]=1)=[O:3]
Reactant: CCOC(OCC)c1cc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)cs1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4csc(C=O)c4)c3)ncnc21
Temperature: 25 °C

Procedure:
A solution of 3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (70 mg, 0.0001 mol) in THF (1 mL, 0.01 mol) was treated with 1 M HCl in water (400 μL). The reaction was stirred at room temperature. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a semisolid residue (60 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, 1H), 3.73-3.43 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[BH4-]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH4-]
Solvent: CO
Product: COc1ccc(-c2cc(CO)ccc2OC)cc1
Reaction time: 16 h
Yield: 87.2 %

Procedure:
A solution of 4-methoxy-3-(4-methoxyphenyl)benzenecarboxaldehyde (1 g, 4.13 mmol) in methanol (12 mL) was treated with polymer-supported borohydride (10.3 mmol) and the mixture shaken for 16 hours. The resin was then filtered and the filtrate concentrated under reduced pressure to afford 0.88 g of title compound.