Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][O:17][CH2:18][CH:19]=[CH2:20])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26](Cl)=[O:27].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:18]([O:17][CH2:16][C:9]1[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([NH:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([CH3:22])[CH:24]=1)=[O:21])[CH:19]=[CH2:20]
Reactant: C=CCOCc1c(OC)cccc1C(=O)NNC(C)(C)C
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C=CCOCc1c(OC)cccc1C(=O)NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a flask containing 2.0 g (0.0068 mol) of 2-allyloxymethyl-3-methoxy-benzoic acid N′-tert-butyl-hydrazide dissolved in 15 mL of CH2Cl2, was added 1.27 g (0.0075 mol) of 3,5-dimethylbenzoyl chloride in 10 mL of CH2Cl2 and 2.84 g of K2CO3 (0.02 mol) in 30 mL of H2O. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted and partitioned, and the organic phase was dried and solvent was removed in vacuio. The product was purified by silica gel chromatography; eluting in 25% ethyl acetate:hexane fractions, to yield 2.40 g of pure 3,5-dimethyl-benzoic acid N′-(2-allyloxymethyl-3-methoxy-benzoyl)-N-tert-butyl-hydrazide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.2 (t, 1H) 7.1 (s, 1H), 7.05 (d, 2H), 6.95 (m, 2H), 5.9 (m, 1H), 5.2-5.3 (q, 2H), 4.5 (d, 2H), 3.9 (m, 2H), 3.80 (s, 3H), 2.245 (s, 6H), 1.547 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9]C(=O)C(F)(F)F)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.CO.C([O-])([O-])=O.[K+].[K+]>O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: O=C(Nc1cc(F)c(Br)cc1[N+](=O)[O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To N-(4-bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.5 g, 10.5 mmol) was added CH3OH (30 mL) followed by 1.0 M K2CO3 (10.5 mL, 10.5 mmol), and the solution was stirred for 30 minutes (Charifson, P. S.; et al. J. Med. Chem. 2008, 51, 5243-5263). The solution was diluted with H2O and stirred for 1 hour. The resulting orange solid was collected by filtration and dried in a vacuum oven to give the title compound (2.1 g, 8.8 mmol, 84%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16]O)[CH2:5]1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][Br:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)N1CC(CCO)c2c(C)cc(C)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=O)N1CC(CCBr)c2c(C)cc(C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
1-Acetyl-3-(2-hydroxyethyl)-4,6-dimethylindoline (7.0 g) and CBr4 (9.9 g) were dissolved in CH3CN (70 ml), and Ph3P (9.4 g) was added, which was followed by stirring at room temperature for 30 min. CH3CN was evaporated under reduced pressure. AcOEt (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=50/1-10/1) to give 5.4 g of 1-acetyl-3-(2-bromoethyl)-4,6-dimethylindoline.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:10]([OH:18])(=[S:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].Cl>C(O)C>[C:10]([S:17][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])(=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CNC(=O)CCl
Reactant: OC(=S)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)CSC(=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirring solution under argon at 0° C. of (1.50g, 10mmoles) N-chloroacetylglycine in (25 mL) ethanol was added (1.41 ml, 12 mmoles) thiobenzoic acid, followed by (7.0 mL, 3N, 21 mmoles) potassium hydroxide over 3 minutes. The reaction was allowed to heat to room temperature for 20 minutes followed by reflux under argon at 50° C. for 2 hours. The reaction was cooled to room temperature and acidified with (5 mL, 2N) hydrochloric acid. The ethanol was rotavapped off to leave N-(S-benzoylmercaptoacetyl)-glycine (m.p. 140.5°-141.5° C.), a white solid, which was washed with water, filtered, and dried in vacuo (2.46g, 98% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[C:9]([N:8]([CH3:12])[C:5]1[N:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(C)c1ccc(N)cn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of N-(5-aminopyridin-2-yl)-N-methylacetamide (1.00 g, 6.06 mmol) and pyridine (1.47 ml, 18.2 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.25 ml, 9.09 mmol) with ice-cooling, the mixture was stirred for 0.5 hour with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (1.08 g, 52.4%) as a solid.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[N:3]1.S(=O)(=O)(O)O.[CH3:15]O>>[OH:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:15])=[O:8])[CH:4]=[N:3]1
Reactant: CO
Reactant: O=C(O)c1cnn(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnn(O)c1
Yield: 91 %

Procedure:
90 g of 1-hydroxypyrazole-4-carboxylic acid (for preparation, see corresponding German Patent Application No. P 35 32 879.7) are suspended in 500 ml of methanol, and 10 ml of concentrated sulfuric acid are added. The mixture is then refluxed for 12 hours, the methanol is distilled off under reduced pressure, the solid residue is stirred in 400 ml of water, the solution is brought to pH 3 with sodium hydroxide solution, and the product is filtered off under suction and washed with water. The mother liquor is evaporated down, and a further crystalline fraction is obtained. The combined products are dried under reduced pressure to give 91 g (91% of theory) of methyl 1-hydroxypyrazole-4-carboxylate of melting point 175°.181° C. NMR (DMSO-D6): 8.35 s [1]; 7.82 s [1]; 3.80 s [3].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:1]
Reactant: Cc1ccc(CO)c(C(=O)O)c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Cc1ccc(C=O)c(C(=O)O)c1
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a homogeneous, colorless solution of 2-(hydroxymethyl)-5-methylbenzoic acid (0.6325 g, 3.81 mmol) in THF (35 mL) under nitrogen was added MnO2 (4.96 g, 57.1 mmol), and the reaction was stirred overnight. Additional MnO2 (˜3 g) was added, and the reaction was stirred overnight. The mixture was filtered through a pad of CELITE® and rinsed with THF. The filtrate was concentrated in vacuo to give the desired product (0.3302 g, 2.011 mmol, 52.8% yield) as an off-white solid.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([CH:39]4[CH2:41][CH2:40]4)=[CH:34][N:33]=3)[CH2:28][CH2:27]2)=[O:25])=[C:20]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:19]=1>>[CH:39]1([C:35]2[CH:36]=[C:37]([CH3:38])[C:32]([N:29]3[CH2:30][CH2:31][N:26]([C:24]([C:21]4[CH:22]=[CH:23][C:18]([N:11]5[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]5(=[O:15])=[O:16])=[CH:19][C:20]=4[S:42]([CH3:45])(=[O:44])=[O:43])=[O:25])[CH2:27][CH2:28]3)=[N:33][CH:34]=2)[CH2:40][CH2:41]1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3[C@H](CO)CCS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 31 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (241 mg) described in Preparation Example 1 and (4-bromo-2-methanesulfonylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (478 mg) described in Preparation Example 126 and by the reaction and treatment in the same manner as in Example 32, the title compound (170 mg) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@:8]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C@H:12]([CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C@@H:11]([CH3:19])[O:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@:8]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:9][O:10][C@H:11]([CH3:19])[C@H:12]1[CH:13]([OH:18])[C:14]([F:17])([F:15])[F:16]
Reactant: C[C@H]1OC[C@@](NC(=O)OC(C)(C)C)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1OC[C@@](N)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Reaction time: 16 h
Yield: 1334.3 %

Procedure:
[(3S,4R,5R)-3-(2-Fluoro-phenyl)-5-methyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-tetrahydro-furan-3-yl]-carbamic acid tert-butyl ester (Preparation Example 30-(3)) (1.20 g, 0.23 mmol) was dissolved in DCM (20 ml). TFA (10 ml) was added. The reaction mixture was stirred overnight (16 h). The reaction was then concentrated, 10 ml of aqueous saturated sodium carbonate was added then extracted with DCM (2×40 ml). 900 mg (86%) of a mixture of the title compound (85%) and its epimer at the CF3 position (15%) were isolated.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[C:6]([F:18])[CH:5]=1)[CH3:3].Cl[C:20]1[N:25]=[C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][O:28][C:27]2=[O:34])[C:23]([F:35])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:35][C:23]1[C:24]([N:26]2[C@@H:30]([CH:31]([CH3:32])[CH3:33])[CH2:29][O:28][C:27]2=[O:34])=[N:25][C:20]([NH:1][C@H:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:11])=[C:6]([F:18])[CH:5]=2)[CH3:3])=[N:21][CH:22]=1
Reactant: C[C@H](N)c1ccc(C(=O)N2CCCCC2)c(F)c1
Reactant: CC(C)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1nc(N[C@@H](C)c2ccc(C(=O)N3CCCCC3)c(F)c2)ncc1F
Temperature: 107.5 °C
Yield: 12.5 %

Procedure:
To (S)-(4-(1-aminoethyl)-2-fluorophenyl)(piperidin-1-yl)methanone (0.019 g, 0.076 mmol) was added (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (0.030 g, 0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190 mmol). The reaction was heated at 105-110° C. for 8 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 4.5 mg of (S)-3-(5-fluoro-2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as TFA Salt. LCMS m/z 474.2 (M+H)+, Rt 0.91 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:19]1([CH2:18][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH2:5][CH2:4][O:3][C:2]([CH3:15])([CH3:1])[C:7]2=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C)OCCc2c1[nH]c1ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCCc2c1n(Cc1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3,4,9-Tetrahydro-1,1-dimethylpyrano[3,4-b]indole (5 g, 25 mmole, described by C. A. Demerson et al., cited above) was added portionwise to a suspension of sodium hydride (3 g, 58% dispersion in mineral oil) in 25 ml of dry dimethylformamide. This was stirred at room temperature for one hour. Benzyl chloride (3.8 g, 30 mmole) was added dropwise with ice cooling. The temperature was raised to 40° C. for 30 min. The reaction was poured into ice-water and the mixture was extracted with diethyl ether, washed twice with water, dried and evaporated. The solid residue (10 g) was chromatographed on silica gel using 10% ethyl acetate in benzene to afford 4.5 of white solid which was crystallized from butanol to give 9-phenylmethyl-1,3,4,9-tetrahydro-1,1-dimethylpyrano[3,4-b]indole, mp 132°-134° C.
Reaction SMILES: [CH3:1][Si](C#C)(C)C.C([Li])CCC.[C:12]([O:16][C:17](=[O:39])[NH:18][C@:19]([CH:37]=O)(C)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1)([CH3:15])(C)C>C1COCC1>[C:15]([CH:12]1[O:16][C:17](=[O:39])[NH:18][C@@:19]1([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=1)[CH3:37])#[CH:1]
Reactant: CCCCCCCOc1ccc(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CC1OC(=O)N[C@]1(C)CCc1ccc(OCCCCCCC)cc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of trimethylsilylacetylene (0.18 ml, 1.27 mMol) in THF (18 ml) at −78° C. is added n-Butyllithium (0.49 ml, 2.5 M in cyclohexane). After 5 minutes, [(R)-1-Formyl-3-(4-heptyloxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (200 mg, 0.51 mMol) in THF (2 ml) is added and the reaction is stirred at −78° C. for 5 hours. After that time, the cooling is removed and the reaction is stirred for 16 hours at RT. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted with AcOEt (3 times). The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 8%-45% AcOEt in heptane gives (R)-5-Ethynyl-4-[2-(4-heptyloxy-phenyl)-ethyl]-4-methyl-oxazolidin-2-one and its C5 epimer.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]([O:9][CH:10]([Cl:12])[CH3:11])=[O:8].CN1CCOCC1>C(Cl)Cl>[C:7](=[O:8])([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][CH:10]([Cl:12])[CH3:11]
Reactant: CC(C)(C)S
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(Cl)OC(=O)SC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A solution of tert-butyl thiol (180 g, 2 mol) and 1-chloroethyl chloroformate (284 g, 2 mol) in CH2Cl2 (1 L) was cooled to 0° C. in an ice-water bath. N-Methylmorpholine (212.1 g, 2.1 mol) was added dropwise over a period of 1 h and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with excess CH2Cl2 (2 L), washed with water (2×1 L), saturated bicarbonate solution (1 L) and brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation (135° C./20 Torr) to provide the title compound (3) as a colorless liquid (350 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 1.50 (s, 9H), 1.79 (d, J=6 Hz, 3H), 6.57 (q, J=5.6 Hz, 1H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH:6]1([N:11]2[C:16]3[N:17]=[C:18]([S:21][CH3:22])[N:19]=[CH:20][C:15]=3[C:14](O)=[CH:13][C:12]2=[O:24])[CH2:10][CH2:9][CH2:8][CH2:7]1>ClC(Cl)C>[Br:3][C:14]1[C:15]2[CH:20]=[N:19][C:18]([S:21][CH3:22])=[N:17][C:16]=2[N:11]([CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:12](=[O:24])[CH:13]=1
Reactant: CSc1ncc2c(O)cc(=O)n(C3CCCC3)c2n1
Reactant: O=P(Br)(Br)Br
Solvent: CC(Cl)Cl
Product: CSc1ncc2c(Br)cc(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 50 %

Procedure:
Phosphorus oxybromide (11.3 mL) was added to a mixture of 8-cyclopentyl-5-hydroxy-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.56 g, 9.23 mmol) in dichloro-ethane (13 mL) at RT. The reaction mixture was heated to 100° C. in a microwave reactor for 1 h, then cooled to RT. The resulting mixture was partitioned between EtOAc (200 mL) and NaHCO3 (sat'd aq, 200 mL), and the aqueous layer extracted with EtOAc (100 mL). The combined organic layers were washed with NaHCO3 (sat'd aq, 3×100 mL) and water (2×100 mL), dried over MgSO4, filtered and evaporated under reduced pressure to give 1.58 g (50% yield) of 5-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. MS=340, 342 [M+H]+.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[CH:8]=[CH:9][C:2]=12.Cl.[OH-].[Na+]>>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]3)[CH:8]=[CH:9][C:2]=12
Reactant: c1cc2nonc2cc1CCN1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCN(CCc2ccc3nonc3c2)CC1
Yield: 87.9 %

Procedure:
A solution of 8-[2-(benzofurazan-5-yl)ethyl]-1,4-dioxa-8-aza spiro[4.5]decane (20.0 g, 69.1 mmol) in 1N aqueous HCl (200 mL, 200 mmol) was heated to reflux for 1.5 hr. The cooled solution was adjusted to pH 8.5 with 40% aqueous sodium hydroxide and extracted with ethyl acetate (250 mL then 100 mL). The combined extracts were washed twice with 1N aqueous HCl (200 mL combined). The acid layers were heated to reflux for 1 hr and then cooled. Basification as above, extraction into ethyl acetate, drying (Na2SO4), concentration, and trituration with hexanes afforded 1-[2-(benzofurazan-5-yl)ethyl]piperidin-4-one as a solid 14.9 g (88%). HPLC: Rt=3.0 min, 90:10 (0.1% H3PO4 in water: acetonitrile) flow=2.0 mL/min, Waters C18 micro bondapak 25 cmL.
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8]O)[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:43]I>C1COCC1>[F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][I:43])[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: II
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(F)[C@H](O)[C@@H](CI)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
Chiral 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2,4-dione (6.14 g, 23.6 mmol), PPh3 (9 g, 34.4 mmol), imidazole (2.4 g, 34.4 mmol) and dry THF (100 mL) were added into a 3-neck flask bottle (500 mL), the mixture was stirred at 20° C. under nitrogen atmosphere for 20 min. Then I2 (6.6 g, 26 mmol) dissolved in dry THF (100 mL) was added into the mixture dropwise at 20° C. during 30 min, after addition, the whole mixture was stirred at 20° C. under nitrogen atmosphere for 18 hrs. TLC showed that the SM was consumed, then water (50 mL) was added into it, the mixture was extracted by EA (150 mL×3), organic layer was washed with brine, dried over Na2SO4, removed solvent by reduced pressure, residue was purified by silica gel chromatography column (DCM:MeOH=100:1 to 50:1) to afford the title compound as a white solid (8.2 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[N:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH:8]3[CH2:15][CH2:16][CH2:17][N:7]3[CH2:6][C:5]2=1.[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:20])[C:10]3[CH2:9][CH:8]4[N:7]([CH2:17][CH2:16][CH2:15]4)[CH2:6][C:5]=3[C:4]=2[CH:3]=1
Reactant: c1cc(C2CO2)ccn1
Reactant: Clc1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1c2c(c3cc(Cl)cnc31)CN1CCCC1C2)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-chloro-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-cyclopenta[b]fluorene (700 mg, 2.82 mmol) in DMF (10 mL) were added portionwise NaH (60%, 338 mg 8.46 mmol) and 4-oxiranyl-pyridine (511 mg, 3.38 mmol). The reaction mass was stirred at RT for 16 h. The progress of reaction was monitored by LCMS. The reaction mass was quenched with ice cold water (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layer was washed with water (10×100 mL) followed by brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-15% DCM/MeOH) followed by reverse phase HPLC to yield the title compound;
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])=[O:17]
Reactant: Cc1ccccc1CO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: Cc1ccccc1COC(=O)CCC(=O)CN
Reaction time: 96 h

Procedure:
From 2-methylbenzyl alcohol (5.0 g; 41 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 4 days at 100° C. The yield was 0.72 g (44%). Mp 107-109° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](O)=[O:25]>>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: O=C(O)c1ccccn1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccn4)cc23)CC1
Yield: 84.9 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.0 mg (0.15 mMol) pyridine-2-carboxylic acid, 14.2 mg (85%) of the title compound were recovered.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.CS([C:19]1[N:20]=[CH:21][C:22]2[N:27]=[C:26]([C:28]3[CH:48]=[C:47]([CH3:49])[C:31]([O:32][CH:33]4[CH2:36][CH:35]([C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[CH2:34]4)=[C:30]([CH3:50])[CH:29]=3)[O:25][C:23]=2[N:24]=1)(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:19]1[N:20]=[CH:21][C:22]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH3:50])[C:31]([O:32][CH:33]4[CH2:36][CH:35]([C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[CH2:34]4)=[C:47]([CH3:49])[CH:48]=3)[O:25][C:23]=2[N:24]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1cc(-c2nc3cnc(S(C)(=O)=O)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(Oc4cccc(Cl)c4)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
48 mg of potassium carbonate and 20 mg of 3-chlorophenol were added to a solution of 70 mg of benzyl 3-[4-(5-methanesulfonyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]cyclobutanecarboxylate in 5 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1.5 h and at 60° C. for a further 4 h. For work-up, 10% strength aqueous citric acid solution was added, and the reaction was extracted with dichloromethane. The combined organic phases were concentrated and dried under reduced pressure. This gave 77 mg (100%) of the title compound, which was reacted further without any purification.