Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.Cl>C(O)C.O1CCOCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2Br)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Fc1ccc(Br)c(OC2CCNCC2)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(2-bromo-5-fluorophenoxy)piperidine-1-carboxylate from Step 1, Method (i), was dissolved in ethanol (200 mL), cooled to −78° C. and treated with 4 N HCl in dioxane (450 mL). The reaction was warmed and stirred overnight at room temperature. The solvent was removed under reduced pressure and the mixture partitioned between 1 N NaOH (750 mL) and a 1:1 mixture of ether-hexane. After several extractions, the organics layers were combined and evaporated to dryness. The crude material was dissolved in heptane (1 L) and a white precipitate was filtered and discarded. The heptane layer was diluted with ether and treated with 4 N HCl in dioxane (100 mL). The resulting precipitate was collected by filtration and washed three times with a 1:1 mixture of ether-hexane. The salt was partitioned again between 1 N NaOH (500 mL) and a 1:1 mixture of ether-hexane. After several extractions, the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude material was dissolved into heptane (2 L) and washed four times with 1 N NaOH (250 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give the title compound as colorless oil.
Reaction SMILES: [Cl-].[NH4+].O.[OH:4][CH2:5][CH2:6][N:7]([CH2:19][CH2:20][OH:21])[C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:9]=1[C:10]#[N:11]>[Fe].C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:8]([N:7]([CH2:19][CH2:20][OH:21])[CH2:6][CH2:5][OH:4])=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N(CCO)CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1N(CCO)CCO
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Subsequently, ammonium chloride (0.9 g) and iron powder (4.5 g) were added to a mixed solvent of water (10 ml) and ethanol (30 ml), and the mixture was heated to 65° C. Then, 2-bis(2-hydroxyethyl)amino-5-nitrobenzonitrile (11 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide ice solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (8 g), melting point: 38° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([OH:15])=O.BrC1C=CSC=1C(Cl)=O.Cl.[CH3:26][NH:27][O:28][CH3:29].C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:13]([C:9]1[S:10][CH:11]=[CH:12][C:8]=1[Br:7])=[O:15]
Reactant: CNOC
Reactant: O=C(O)c1sccc1Br
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1sccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1sccc1Br
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Oxalyl chloride (0.601 mL, 6.99 mmol, 1.2 eq) is added to a mixture of 3-bromothiophene-2-carboxylic acid (1.20 g, 5.80 mmol), N,N-dimethylformamide (several drops, catalytic amount), and anhydrous dichloromethane (25 mL) at ambient temperature under nitrogen over 20 minutes. The reaction is stirred for 17 hours, purged with nitrogen, and concentrated under reduced pressure to afford a tan solid. The crude 3-bromothiophene-2-carbonyl chloride is dissolved in dichloromethane (25 mL) and added dropwise, over 10 minutes, to a 0° C. solution of N,O-dimethylhydroxylamine hydrochloride (843 mg, 8.64 mmol), diisopropylethylamine (2.50 mL, 14.3 mmol), and dichloromethane (25 mL). The reaction is allowed to gradually warm to ambient temperature overnight. The reaction is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product is purified by chromatography on silica, eluting with 1:1 ethyl acetate/heptane, to give 3-bromo-thiophene-2-carboxylic acid methoxy-methyl-amide, as a white solid: TLC Rƒ0.33 (silica, 1:1 ethyl acetate/heptane); LC/MS: (M+H 249.94, RT=2.18 minutes); 1H NMR [(CD3)2SO), 300 MHz]: δ 7.85 (d, 1H, J=5.3 Hz), 7.17 (d, 1H, 5.3 Hz), 3.62 (s, 3H), 3.24 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CI
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C#N)ccc21
Reaction time: 0.5 h
Yield: 122 %

Procedure:
To a solution of 1H-indole-5-carbonitrile (600 mg, 4.2 mmol) in DMF (5 mL) at 0° C. was added NaH (201 mg, 60% in oil, 8.4 mmol) with vigorous stirring. The solution was stirred 30 min, then iodomethane (1.8 g, 12.6 mmol) was added. The reaction mixture was stirred at RT for 4 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to afford 800 mg of 1-methyl-1H-indole-5-carbonitrile (294) as white solid: MS (ESI) m/z=157.3 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCOc2cc(CO)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(7-Formyl-chroman-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 1, Step G) (1.83 g, 3.56 mmol) was dissolved in a 1:1 solution of THF and MeOH (100 mL). The solution was cooled to 0° C. and NaBH4 (0.135 g, 3.56 mmol) was added. The reaction was stirred for 30 min. The volatiles were removed in vacuo and the resulting residue was dissolved in EtOAc and washed sequentially with a saturated NaHCO3 solution and brine. The aqueous phases were extracted once with EtOAc. The organic phases were combined, dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound. MS (ESI) m/z 517 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:23][C:24]1([F:28])[CH2:27][NH:26][CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:24]1([F:28])[CH2:27][N:26]([C:19](=[O:21])[CH2:18][O:17][CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[CH2:25]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)COC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COC1CCN(C(=O)OCc2ccccc2)CC1)N1CC(F)(F)C1
Reaction time: 8 h
Yield: 65 %

Procedure:
2-(1-(Benzyloxycarbonyl)piperidin-4-yloxy)acetic acid (4.12 g, 14.05 mmol), 3,3-difluoroazetidine hydrochloride (1.4 g, 10.81 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (3.47 g, 10.81 mmol) were dissolved in DMF (50 mL), to this was added DIPEA (4.91 mL, 28.10 mmol) and the reaction was stirred overnight. The solvent was evaporated and the reaction mixture was quenched with 2M NaOH (50 mL), extracted with Et2O (3×50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a yellow gum (2.59 g, 65.1% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.67-1.49 (2H, m), 1.90-1.81 (2H, m), 3.26-3.19 (2H, m), 3.58-3.51 (1H, m), 3.84-3.78 (2H, m), 4.13 (2H, s), 4.36 (2H, t), 4.60 (2H, t), 5.12 (2H, s), 7.40-7.29 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]2[C:11]3([CH2:30][O:31][C:5]=2[CH:4]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13](CC1C=CC(OC)=CC=1)[C:12]3=[O:29].FC(F)(F)S(O)(=O)=O>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]2[C:11]3([CH2:30][O:31][C:5]=2[CH:4]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]3=[O:29]
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(OC)c(C#N)cc43)c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C#N)C1(CO2)C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a stirred solution of 6-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.50 g, 1.2 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added trifluoromethanesulfonic acid (1.0 mL, 11 mmol). The reaction mixture was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 6-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.34 g, 96%): mp 185-186° C.; 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 7.30-7.25 (m, 1H), 7.11-7.03 (m, 2H), 6.97-6.94 (m, 2H), 6.56 (s, 1H), 4.91 (ABq, 2H), 3.90 (s, 3H); MS (ES+) m/z 292.9 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@:8]([S:29]C([C@@]12C(C)(C)C(C)(CC1)C(=O)O2)=O)([CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][O:11]C(=O)C1C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1>CCOCC.C1COCC1>[SH:29][C@@:8]([CH3:7])([CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][OH:11]
Reactant: CCC[C@@](C)(CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)SC(=O)[C@@]12CCC(C)(C(=O)O1)C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC[C@](C)(S)CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a suspension of 0.28 g (7.5 mmol) of LiAlH4 in 10 ml of Et2O was added a solution of 1.3 g of (1S,3S)-3,5-dinitro-benzoic acid 3-methyl-3-(4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonylsulfanyl)-hexyl ester of step (b) in 10 ml of THF. The reaction mixture was stirred at room temperature overnight, quenched with 20 ml of water and filtered over Celite. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was distilled (bulb to bulb, 0.06 Torr, up to 190° C.) and gave 100 mg (27%) of (S)-3-mercapto-3-methyl-hexan-1-ol in form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[S:11]([CH3:14])(=[O:13])=[O:12].[H-].[Na+].Br[CH2:18][C:19]#[N:20].O.C(OCC)(=O)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:18][C:19]#[N:20])[CH:8]=[C:7]2[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1c[nH]c2c(Cl)cccc12
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cn(CC#N)c2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 7-chloro-3-methanesulfonyl-1H-indole (2.21 g, 0.00962 mole) of Step 6 was dissolved in 20 ml dry N-methylpyrrolidinone and cooled to 0° C. under a nitrogen atmosphere. Sodium hydride (60% in oil, 0.46 g, 0.0115 mole) was added in portions with stirring and the reaction mixture was allowed to stir until bubbling ceased. Bromoacetonitrile (1.27 g, 0.0106 mole) was added all at once and the resulting solution was stirred and allowed to reach room temperature. After 1 h, the reaction mixture was poured into water-ethyl acetate and the organic layer was washed three times with brine and dried over magnesium sulfate. Evaporation to dryness gave a residue of 3.31 g which was purified by flushing through an alumina (6% water) column using 3:7 and 1:1 ethyl acetate-hexane to elute the product. The purified (7-chloro-3-methanesulfonyl-indol-1-yl)-acetonitrile was crystalline and weighed 2.111 g after thoroughly drying.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:31])[C:12]([N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[CH:3][CH:2]=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH3:31])[C:12]([N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[CH:5][CH:6]=1
Reactant: COc1ccc(S(=O)(=O)N(C)c2c(C)cc(C#Cc3ccc(-c4ccccc4)cc3)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(C)c2c(C)cc(CCc3ccc(-c4ccccc4)cc3)cc2C(=O)O)cc1
Yield: 85.8 %

Procedure:
To a solution of 0.20 g (0.391 mmol) of the product of Example 352 in 25 mL of methanol and 10 mL of ethyl acetate was added 0.050 g of 10% palladium on carbon. The mixture was hydrogenated in a Parr apparatus at 30 psi of hydrogen for 5 h, then filtered through Celite. The Celite pad was washed with 100 mL of methanol and 100 mL of ethyl acetate and the filtrate was concentrated in vacuo. The residue was trituratedwith ether to give 0.173 g (86%) of the carboxylic acid as a pale yellow solid. Electrospray Mass Spec: 514.2 (M-H)-.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=O)=O.C(O)(=O)C.[OH:26][C@H:27]1[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[CH2:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([N:29]2[CH2:30][C@@H:31]([OH:32])[C@H:27]([OH:26])[CH2:28]2)[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Oc1cccc(Cc2ccccc2)n1)C(F)(F)F
Reactant: O[C@@H]1CNC[C@H]1O
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: O[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 6 h
Yield: 55.6 %

Procedure:
To a mixture of 11.3 g of 2-benzyl-6-pyridyl trifluoromethanesulfonate, 11.3 g of (3R,4R)-3,4-dihydroxypyrrolidine acetate (synthesized from D-tartaric acid as a starting material, Angew. Chem. Int. Ed. Engl., 23(6), 435, 1984) and 10 ml of N-methylpyrrolidone was added dropwise 11 ml of 1,8-diazabicyclo[5.4.0]-7-undecene under nitrogen atmosphere in an oil bath at 100° C., followed by heating under stirring for 6 hours. After standing to cool, the reaction mixture was extracted with ethyl acetate-water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate), to give 5.35 g of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:13]#[C:14]Br>>[O:6]([CH2:5][C@@H:2]1[CH2:3][O:4][C:14]([NH2:13])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N[C@@H](CO)COc1ccccc1
Reactant: N#CBr
Product: NC1=N[C@H](COc2ccccc2)CO1

Procedure:
In analogy to example 1b (S)-2-amino-3-phenoxy-propan-1-ol was reacted with cyanogen bromide to give (R)-4-phenoxymethyl-4,5-dihydro-oxazol-2-ylamine. Colourless gum. MS (ISP): 193.1 ([M+H]+))
Reaction SMILES: CS[C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:3]2[N:13]3[C:14]4[N:9]([C:10]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=5)=[CH:11][CH2:12]3)[N:8]=[CH:7][C:6]=4[C:5](=[O:25])[N:4]=2)=[CH:29][CH:28]=1
Reactant: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Reactant: NCc1ccc(Cl)cc1
Product: O=c1nc(NCc2ccc(Cl)cc2)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2

Procedure:
A 400 mg amount of 5-(methylthio)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacena-phthylen-3-one (prepared as described in Example 9) in 25.0 mg of 4-chlorobenzylamine was heated at 70° C. for 36 hours. The precipitate which formed was collected by filtration to give the product of the example as a white solid, m.p. 281°-282° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: O=Cc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 67.6 %

Procedure:
54.2 g of 4-hydroxymethylbenzaldehyde, together with 40 g of triethylamine, are dissolved in 350 ml of dichloromethane. After the dropwise addition of 31.2 g of acetyl chloride at 0° to 5° C., the reaction mixture is allowed to stand overnight at room temperature. Thereafter, the precipitated triethylammonium chloride is filtered off under suction, and the filtrate is extracted 3 times with saturated bicarbonate solution. After it has been dried with sodium sulphate, the residue is distilled in a high vacuum. 47.9 g of a colorless solid are obtained in this manner.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[S:7][S:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][S:17][S:18]Cl>ClCCCl>[CH2:1]([N:3]([S:7][S:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][S:17][S:18][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: ClSSSCCCCCCSSSCl
Solvent: ClCCCl
Product: CCN(CC)SSSCCCCCCSSSN(CC)CC

Procedure:
20.0 ml (152 mmol) of diethylamine are used as initial charge in 1,2-dichloroethane in an inertized three-necked flask with dropping funnel, reflux condenser with hose coupling at its upper end, a tap with hose coupling and a Teflon stirrer bar, in a countercurrent of argon. 10.4 g (29.7 mmol) of 1,6-bis(chlorotrisulphanyl)hexane in 50 ml of 1,2-dichloroethane are then slowly added dropwise, with stirring. The reaction mixture is stirred at room temperature for 4 hours. The resultant salt is filtered off, and the organic phase is washed three times with water and dried over sodium sulphate. After removal of the solvent on a rotary evaporator and drying in the vacuum generated by a rotary-vane pump, 1,6-bis(diethylaminotrisulphanyl)hexane precipitates in the form of a yellow oil. The crude yield is 5.32 g (82%). Elemental analysis was carried out on the crude product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:4][CH:5]=[N:6][CH:7]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[N:1]1[C:2]2[CH:7]=[N:6][CH:5]=[N:4][C:3]=2[N:8]([CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ncncc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1nnc2cncnc21
Reaction time: 1 h
Yield: 114.7 %

Procedure:
1,1-Dimethylethyl (2S)-2-{[(5-amino-4-pyrimidinyl)amino]methyl}-1-pyrrolidinecarboxylate (1.6633 g, 5.67 mmol) and sodium nitrite (469 mg, 6.80 mmol) were dissolved in a mixture of acetic acid (5 mL) and water (8 mL), and the mixture was stirred vigorously for 1 h. The solution was concentrated in vacuo to provide 1,1-dimethylethyl (2S)-2-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-1-pyrrolidinecarboxylate (1.98 g, >99%). LCMS: (M+H)+: 305.2.
Reaction SMILES: [OH:1]O.[CH3:3][S:4][CH2:5][C:6]1[N:11]=[C:10]([O:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[C:9]([CH:18]([CH3:20])[CH3:19])=[C:8]([CH3:21])[N:7]=1>C(O)(=O)C>[CH3:3][S:4]([CH2:5][C:6]1[N:11]=[C:10]([O:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[C:9]([CH:18]([CH3:19])[CH3:20])=[C:8]([CH3:21])[N:7]=1)=[O:1]
Reactant: OO
Reactant: CSCc1nc(C)c(C(C)C)c(OC(=O)N(C)C)n1
Solvent: CC(=O)O
Product: Cc1nc(CS(C)=O)nc(OC(=O)N(C)C)c1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
3.4 g (0.05 mol) of 50% strength hydrogen peroxide were added to a solution of 14.2 g (0.05 mol) of N,N-dimethyl-carbamic acid O-(2-methylthiomethyl-5-iso-propyl-6-methyl-pyrimidin-4-yl) ester in 50 ml of glacial acetic acid at 5°-10° C. The mixture was subsequently stirred at room temperature for 6 hours and the solvent was then distilled off in vacuo. The residue was dissolved in 100 ml of methylene chloride and the methylene chloride solution was washed with a solution of 10 g of potassium carbonate in 15 ml of water. The organic phase was separated off and dried over sodium sulphate. The solvent was then distilled off in vacuo. 11 g (74% of theory) of N,N-dimethyl-carbamic acid O-(2-methylsulphinylmethyl-5-iso-propyl-6-methyl-pyrimidin-4-yl) ester were thus obtained in the form of beige crystals with a melting point of 80° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].Br[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)(C)C>[NH2:26][C:25]1[CH:27]=[CH:28][C:22]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:23][CH:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-[(tert-butyl amino)sulfonyl]phenyl boronic acid (6.00 g, 23.35 mmol) in 120 ml toluene was added water (16 ml), isopropanol (60 ml), and NaOH (40 ml, 5M aqueous solution). To this were added 4-bromoaniline and Pd(Ph3P)4. This heterogeneous mixture is then refluxed for 6 hr, then stirred at room temperature over night before refluxing for another 1.5 hr. The reaction mixture is then extracted with water and ethyl acetate. The aqueous layer is extracted twice with ethyl acetate. The organic layers are then dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by silica gel flash chromatography. The desired product can be eluded with 30% ethyl acetate in hexanes and concentrated to an orange solid (5.06 g, 16.65, 71%). ES-MS(M+H)+=305.