Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:35](Cl)(=[O:37])=[O:36])[CH:33]=2)[NH:28][N:27]=1.C([O-])(O)=O.[Na+].CCCCCC>ClCCl>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:9]([OH:16])[CH2:10][N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[S:35]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH3:25])(=[O:37])=[O:36])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cc1n[nH]c2ccc(S(=O)(=O)Cl)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1n[nH]c2ccc(S(=O)(=O)N(CC(C)C)CC(O)C(Cc3ccccc3)NC(=O)OC(C)(C)C)cc12
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester 15 (60 mg, 0.18 mmol) and 3-methyl-1H-indazole-5-sulfonyl chloride (50 mg, 0.22 mmol) in 2 mL dichloromethane was added a 70 ul solution of a saturated NaHCO3 and 30 mg NaHCO3 and stirred overnight. The product was purified by preparative TLC using 1:1 ethyl acetate: hexane to give 95 mg product (99% yield). MS 531 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[C:15]([OH:17])=[O:16].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[C:15]([O:17][CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=1)=[O:16]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(Br)cc2c1NCCC2C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(Br)cc2c1NCCC2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromo-1,2,3,4-tetrahydroquinoline-4,8-dicarboxylic acid (10.2 g), benzyl bromide (9 ml) and potassium carbonate (10 g) in DMF (30 ml) was stirred at room temperature for 3 hours and filtered. To the filtrate was added a mixture of ethyl acetate-benzene (1:1, 300 ml). The mixture was washed with water, dried over anhydrous sodium sulfate and concentrated to give oily objective compound (17.44 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=O.[F:25][C:26]([F:34])([F:33])[C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:25][C:26]([F:34])([F:33])[C:27]([C:28]1[C:29]([CH3:30])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)=[O:32]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(OC(F)(F)F)ccc2N)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 45 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-methanesulfonyl-phenyl)-methanone [example A 13] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 45%; MS: m/z=477 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (57 mg, 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCCCC2)cc1
Reaction time: 12 h
Yield: 60.5 %

Procedure:
The general procedure from Example 1 was followed using 4-methyl-chlorobenzene (152 mg, 1.2 mmol) and piperidine (100 μl, 1.0 mmol) with Pd2 (dba)3 (20 mg, 0.0218 mmol) and (Me3C)2PH(O) (14.5 mg, 0.0878 mmol) and NaOtBu (144 mg, 1.5 mmol) in 3.0 mL of toluene. After 12 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 106 mg (61% yield) of N-(4-methylphenyl)piperidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 6.92 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 2.95 (t, J=5.5 Hz, 4H), 2.13 (s, 3H), 1.58 (m, 4H), 1.43 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ 150.3, 129.5, 128.6, 116.9, 51.2, 25.9, 24.3, 20.3 ppm. MS: Calculated for C12H17N(M+): 175.1. Found: 176.1 (M+ +H).
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)(O)[O-].[K+].[I-].[K+]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([F:15])([F:1])[CH:12]([F:13])[F:14])=[CH:6][CH:7]=2)[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: Nc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCNc1ccc(OCC(F)(F)C(F)F)cc1
Yield: 41.1 %

Procedure:
A mixture of 4-(2,2,3,3-tetrafluoropropoxy)aniline (7.4 g), N-(2-bromoethyl)phthalimide (9.0 g), potassium bicarbonate (6.9 g), potassium iodide (5.5 g) and N,N-dimethylformamide (80 ml) are refluxed for 22 hours. The solvent was distilled off under reduced pressure. To the residue, ice-water (200 ml) and ethyl acetate (200 ml) were added and fractionated. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate:hexane=1:2 v/v) and recrystallized from ethyl acetate-diisopropyl ether to give N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (5.4 g) as white crystals.
Reaction SMILES: C([O:8][C:9]1[C:26]([N:27]([CH3:29])[CH3:28])=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[CH3:29][N:27]([CH3:28])[C:26]1[C:9]([OH:8])=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]1=[O:30]
Reactant: CN(C)c1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 3-benzyloxy-2-dimethylaminoestra-1,3,5(10)-trien-17-one (81, 0.666 g, 1.65 mmol) in THF (30 mL) was added 10% palladium on carbon (0.200 g). The reaction mixture was stirred for 1 h under a hydrogen atmosphere at room temperature. After the catalyst was filtered, the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (3:1→2:1, v/v) to afford 0.462 g of 82 (89% yield) mp: 160-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].CI.CCOC(C)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(O)c(Br)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of 2-bromo-4-(methylsulfonyl)phenol (243 mg, 0.968 mmol) and K2CO3 (201 mg, 1.45 mmol) in DMF (2 mL) was added CH3I (0.0660 mL, 1.06 mmol). The reaction was stirred at room temperature for overnight, diluted reaction with EtOAc (10 mL) and water (10 mL). The organic layer was separated, and the aqueous layer extracted again with EtOAc (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated, and purified with a silica gel column by ISCO CombiFlash® chromatography eluting with 10%-40% EtOAc/Heptane to afford the desired product (168 mg, 65.5%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH2:16][OH:17])=[CH:10]2)[CH3:2]>ClCCl.[O-2].[Mn+2]>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH:16]=[O:17])=[CH:10]2)[CH3:19]
Reactant: CCN(CC)CCCc1ccc2[nH]c(CO)cc2c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Yield: 86.1 %

Procedure:
Manganese oxide (3.75 g, 43.1 mmol) was added portionwise to [5-(3-diethylamino-propyl)-1H-indol-2-yl]-methanol (660 mg, 2.53 mmol) dissolved in dichloromethane (68 mL) under nitrogen at room temperature. The precipitate was filtered through celite, washing with hot dichloromethane. The filtrate was concentrated to give 563 mg (83%) of 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde as a waxy brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].C([Li])CCC.CCCCCC.[C:20](OCC)(=[O:24])[C:21]([NH2:23])=[O:22].Cl>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[C:3]([Cl:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C:20](=[O:24])[C:21]([NH2:23])=[O:22]
Reactant: CCOC(=O)C(N)=O
Reactant: Clc1ccccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NC(=O)C(=O)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
A stirred solution of 1,2-dichlorobenzene (50.0 g, 0.34 mol) in dried tetrahydrofuran (500 ml) was cooled to -65° C. under N2 and treated dropwise over 1 hour with a solution of n-butyl lithium in hexane (204 ml of 1.72 molar=0.35 mol), with the temperature held below -60° C. After stirring for a further 1 hour the pale yellow solution was treated dropwise with a solution of ethyl oxamate (19.9 g, 0.17 mol) in warm tetrahydrofuran (200 ml) with the reaction temperature held below -60° C. During this addition the reaction mixture changed from yellow through orange to Burgundy red. After stirring for a further 1 hour at -60° C. the mixture was allowed to warm to 0° C. over 2 hours, treated cautiously with water (250 ml) and acidified to pH 6 with hydrochloric acid. The yellow organic phase was separated, washed with brine (2×250 ml), dried (magnesium sulphate) and evaporated to give a yellow solid. This was slurried with ethanol (300 ml) and filtered to give crude 2,3-dichlorophenylglyoxylamide (12.0 g, 32.4%) as an off-white solid m.p. 213-214° C. (ref. m.p. 216-218° C.). Concentration of the ethanolic filtrate to 150 ml afforded a second crop (7.0 g, 18.9%) m.p. 205-206° C.
Reaction SMILES: CO.[C:3]1([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:23](O)/[CH:24]=[CH:25]\[CH2:26][OH:27]>>[C:11]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:27][CH2:26][CH:25]=[CH:24][CH2:23][O:10]1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC/C=C\CO
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: O=C(c1ccccc1)C1(c2ccccc2)OCC=CCO1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
60.8 g (1.9 mols) of methanol were added with stirring to a suspension of 105 g (0.5 mol) of benzil in 107.1 g (0.9 mol) of thionyl chloride, with cooling to a temperature below 10° C. The mixture was initially stirred until room temperature was reached, and then it was stirred for 2 hours at 50° C. 52.8 g (0.6 mol) of cis-2-butene-1,4-diol were added to the clear, pale yellow solution, and volatile products were distilled off at 10 torr and 50° C. The mixture was then stirred for 3 hours at from 60° to 65° C. under normal pressure, 15 g of potassium carbonate and 200 ml of isopropanol were added, and the reaction product was precipitated by the dropwise addition of 100 ml of water. 110.4 g of 2-benzoyl-2-phenyl-4,7-dihydro-1,3-dioxepin were obtained, having a melting point of from 115° to 119° C. After recrystallizing from isopropanol, the melting point was from 118° to 119° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14](Br)=[C:13](Br)[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 315 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([CH3:13])[CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)#[N:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:1]1[N:2]=[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]2=[CH:4][C:3]=1[CH3:13]
Reactant: CC(C#N)CC1CCCCCC1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2c(nc1Br)CCCCC2
Temperature: 15 °C

Procedure:
The product of step (a) (88 g, 0.5 m) in acetic acid (11) was treated with bromine (26 ml, 0.5 m) over 15 minutes, maintaining an internal temperature of ca, 15° C. The mixture was allowed to warm to room temperature overnight. The solvent was evaporated off under reduced pressure and the residue partitioned between water and diisopropyl ether. The organic phase was dried (MgSO4) and evaporated to give a residue which on recrystallising from hexane gave the title compound as white needles, mp 68-70.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:30])[C@@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][C:39]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:30])[C@@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][S:48]([C:39]1[CH:40]=[CH:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=1)(=[O:50])=[O:49])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
A solution of 10 g of (D)-phenylalanine benzyl ester p-toluenesulphonate in 150 ml of methylene chloride is treated with 8.2 ml of triethylamine and cooled to 0° C. 5.8 g of 2-naphthylsulphonyl chloride are added thereto and the mixture is stirred at room temperature for 12 hours. The reaction mixture is evaporated, the residue is taken up in 200 ml of ethyl acetate, the precipitated triethylammonium chloride salt is filtered off under suction and the mother liquor is washed with water. After evaporation of the organic phase and crystallization from hexane there are obtained 9.7 g of N-(2-naphthylsulfonyl)-3-phenyl-D-alanine benzyl ester, m.p. 107° C.
Reaction SMILES: Cl.[F:2][C:3]1[C:13]([F:14])=[C:7]([C:8]([O:10]CC)=O)[C:6]([NH2:15])=[CH:5][CH:4]=1.[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:17]>Cl.C(O)(=O)C>[F:14][C:13]1[C:3]([F:2])=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:10])[NH:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15]2
Reactant: CCOC(=O)c1c(N)ccc(F)c1F
Reactant: CCOC(=O)C#N
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2ccc(F)c(F)c2c(=O)[nH]1
Temperature: 80 °C
Yield: 81.7 %

Procedure:
Ethyl 5,6-difluoroanthranilate hydrochloride (2.50 g, 10.5 mmol) was suspended in 1N hydrogen chloride-acetic acid solution (50 mL), ethyl cyanoformate (1.14 g, 11.6 mmol) was added thereto, and the mixture was stirred under heating at 80° C. for 3 hr. The reaction mixture allowed to cool to room temperature, and concentrated under reduced pressure. The residue was suspended in ethanol, and the insoluble material was collected by filtration to give the title compound as a white powder (2.18 g, 82%).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[N:7]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[CH3:17][O:18][C:19]([C@H:21]1[CH2:26][C@H:25]([NH2:27])[CH2:24][CH2:23][N:22]1C(OC(C)(C)C)=O)=[O:20]>>[CH3:17][O:18][C:19]([C@H:21]1[CH2:26][C@H:25]([NH:27][C:8]2[N:7]=[C:6]([C:5]3[S:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[CH:4]=3)[CH:11]=[CH:10][N:9]=2)[CH2:24][CH2:23][NH:22]1)=[O:20]
Reactant: Clc1nccc(-c2cc3ccccc3s2)n1
Reactant: COC(=O)[C@H]1C[C@H](N)CCN1C(=O)OC(C)(C)C
Product: COC(=O)[C@H]1C[C@H](Nc2nccc(-c3cc4ccccc4s3)n2)CCN1

Procedure:
The title compound was prepared from 4-benzo[b]thiophen-2-yl-2-chloro-pyrimidine and (2R,4R)-4-amino-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester according to Step C of Method A. Yield 45 mg (45%).
Reaction SMILES: [OH-:1].[Na+:2].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]([CH2:23][CH:24]3[CH2:28][C:27](=[O:29])[O:26][CH2:25]3)[CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]3[CH3:22])[CH:7]=[CH:8][CH:9]=1>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]([CH2:23][CH:24]([CH2:25][OH:1])[CH2:28][C:27]([O-:26])=[O:29])[CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]3[CH3:22])[CH:7]=[CH:8][CH:9]=1.[Na+:2]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC3COC(=O)C3)cc2n(C)c1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO)CC(=O)[O-])cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydroxide (2M, 2.00 mL, 4.0 mmol) was added to a suspension of 5-(3-fluorophenyl)-1,3-dimethyl-6-((5-oxotetrahydrofuran-3-yl)methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.35 g, 3.6 mmol) in ethanol (27 mL). The mixture was stirred at room temperature for 2 hours. The solvents were evaporated under vacuum to afford the title compound.
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4]12([C:14](Cl)=[O:15])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2>[OH-].[Na+].CCOCC>[C:4]12([C:14]([NH:1][C:2]#[N:3])=[O:15])[CH2:11][CH:10]3[CH2:9][CH:8]([CH2:7][CH:6]([CH2:12]3)[CH2:5]1)[CH2:13]2
Reactant: N#CN
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: N#CNC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of cyanamide (2.52 g, 0.06 mol) in 24 ml of sodium hydroxide (10%) was added slowly to a solution of 1-adamantanecarbonylchloride (4 g, 0.02 mol) in ether (15 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with ether and the aqueous layer was cooled in ice bath and acidified with hydrochloric acid (10%) to pH 2. The precipitated white solid was filtered, washed with water, later hexanes and dried under high vacuum to give the N-(1-adamantancarbonyl)cyanamide (3.2 g, 78%); m.p. 164–166° C. (lit m.p. 168–170° C.); purity 94% HPLC; 1H-NMR (CD3OD) δ 1.45–2.16 (m, 15H, CH2 and CH).
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][O:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[O:31][CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: COC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (110 mg, 0.24 mmol), 3-methoxytetrahydro-4H-pyran-4-one (80 mg, 0.61 mmol), and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (45 mg after converting to TFA salt) and isomer 2 (35 mg after converting to TFA salt). LCMS calculated for C25H37F3N4O3: (M+H) 498.2; found 498.2 for both isomers.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9](OS(C(F)(F)F)(=O)=O)[C:7]=2[N:8]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C>Cl[Pd]Cl.O1CCOCC1>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:7]=2[N:8]=1
Reactant: COC(=O)c1sc2cnc(SC)nc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Product: COC(=O)c1sc2cnc(SC)nc2c1-c1ccccc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Anhydrous dioxane is added, under argon, to a mixture of 2.5 g of methyl 2-(methylsulfanyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate 4 (example 1) and 0.785 g of phenylboronic acid. After the addition of 250 mg of dichloropalladium (dppf) and 4.09 g of BTPP, the mixture is refluxed for 20 h, and then cooled to ambient temperature. The mixture is filtered on silica gel, elution being carried out with ethyl acetate. The solvent is evaporated off under vacuum and the residue is triturated with an ethyl acetate/heptane mixture so as to obtain 1.6 g of methyl 2-(methylsulfanyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate in the form of a whitish precipitate.