Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31])=[CH:24][CH:23]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:10]([NH:12][C:30](=[O:31])[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)([CH3:34])[CH3:33])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(C)(Nc1ccc(Cl)cc1)C(=O)O
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(NC(=O)C(C)(C)Nc1ccc(Cl)cc1)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Diastereomer α, Section I, Reference Example 1, 0.31 g, 0.94 mmol) and 2-(4-chlorophenylamino)-2-methylpropionic acid (0.20 g, 0.94 mmol) in 5 mL CH2Cl2 was added N-methylmorpholine (0.41 mL, 3.5 mmol) and tris(pyrrolindinyl) phosphonium hexafluorophosphate (0.73 g, 1.4 mmol). After stirring at RT overnight, the reaction mixture was loaded onto a silica gel column eluted with 30% EtOAc in hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.18 (d, 2H), 7.04 (d, 2H), 7.02 (d, 2H), 6.97 (d, 2H), 6.70 (d, 2H), 6.56 (d, 2H), 4.20 (m, 1H), 3.02 (dd, 1H), 2.78 (ddd, 1H), 2.64 (dd, 1H), 1.52 (s, 3H), 1.45 (s, 3H), 0.82 (d, 3H). LC-MS: m/e 489 (M+H)+ (4.3 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CS(C)=O.CCOC(C)=O.O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:14][CH2:15]1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-3-nitropicolinonitrile (5.0 g, 22 mmol) in DMSO (30 mL) was added morpholine (3.8 mL, 44 mmol). The reaction was stirred at rt for 2 h. After this time the reaction was diluted with EtOAc (300 mL) and water (100 mL). The separated organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting solid was washed with MeOH (15 mL) to give 5-morpholino-3-nitropicolinonitrile. Mass Spectrum (ESI) m/e=235.2 (M+1).
Reaction SMILES: C[Si](C#N)(C)C.C(=O)C1C=CC=CC=1.[C:15]([CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:16]>ClCCl.[Ti]>[C:15]([C@H:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:16]
Reactant: N#CC(O)c1ccccc1
Agent: [Ti]
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Solvent: O=Cc1ccccc1
Product: N#C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of L(+)-diisopropyl tartarate (235 mg) in absolute dichloromethane (10 ml), tetaraisopropyl titanate (284 mg) was dropwise added and stirred at room temperature for 30 minutes. After evaporating volatile components off in the same manner as in Example 1, dichloromethane (10 ml) was added to the residue and stirred at room temperature to obtain a homogeneous solution. To the resulting solution, trimethylsilylcyanide (436 mg) and then benzaldehyde (424 mg) were added and stirred at room temperature for 15 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 1 and analyzed by HPLC to reveal that α-cyanobenzyl alcohol containing the R(+) isomer in the enantiomer excess percentage of 88% was produced in the yield of 37% based on the amount of the used benzaldehyde and 148% based on the amount of the used catalyst.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8]O)[CH:2]([CH3:4])[CH3:3].O=S(Cl)[Cl:12]>>[ClH:12].[CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][Cl:12])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CNCCCO
Product: CC(C)CNCCCCl
Product: Cl

Procedure:
3-Aminopropanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydro,1,3-oxazine. The oxazine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxypropylamine. The 3-hydroxypropylamine was reacted with SOCl2 according to Method B9a, Step 3 to give N-isobutyl-3-chloropropylamine HCl salt. The 3-chloropropylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazine.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C(N(CC)CC)C>CC(O)C>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:16][CH2:17][N:18]([C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[NH:26][CH:27]=[N:28]5)[CH2:19][CH2:20]3)[NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: FC(F)(F)Oc1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: FC(F)(F)Oc1cccc(-c2c[nH]c(C3CCN(c4ncnc5nc[nH]c45)CC3)n2)c1
Temperature: 80 °C
Yield: 64.9 %

Procedure:
Add 4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidine (200 mg, 0.642 mmol), 6-chloropurine (105 mg, 0.679 mmol), and triethylamine (95 μL, 0.681 mmol) to 2-propanol (5 mL). Heat the mixture at 80° C. for 3 h. Cool the mixture to room temperature and concentrate in vacuo. Triturate the solid in CH2Cl2 (10 mL). Purify the remaining solid by silica gel chromatography (60 g, eluting with 40% methanol/methylene chloride, 0.500 L) to provide 6-(4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-7H-purine (179 mg, 65%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[F:31]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)=[O:30])=[CH:24][C:23]=1[F:31]
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Nc1ccc(Cl)c(F)c1

Procedure:
1-(4-Chloro-3-fluoro-phenyl)-3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-urea was prepared starting from intermediate D and 4-chloro-3-fluoro-phenylisocyanate. MS calcd. for C23H17Cl2FN3O2 [(M+H)+] 456.1, obsd. 455.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:16][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc(Br)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CCCc1cccc(Br)c1

Procedure:
In the preferred compounds of the invention the two R1 substituents are methyl, and the R2 and R3 substituents are hydrogen. Reaction Scheme 2 illustrates a synthetic process for preparing 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) which serves as a starting material for the synthesis of several preferred compounds of the invention. Thus, referring now specifically to Reaction Scheme 2, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL-H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Compound G is covered by Formula 10 and in accordance with Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the invention.
Reaction SMILES: CN([CH:4]=[O:5])C.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].IC>O>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:5][CH3:4])=[O:10]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 40 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With reference to FIG. 4, DMF (130 mL) was added to a well mixed 2-methyl-3-nitrobenzoic acid 2 (50 g, 0.28 mol) and KHCO3 (84 g, 0.84 mol) solution. Since the mixture became highly viscous, it was heated to 40° C. with manual shaking. Iodomethane (79 g, 0.56 mol) was added via syringe after the gas evolution had ceased. The resulting orange colored solution was stirred for 12 hours at room temperature. The reaction mixture was poured into water (800 mL), and the resulting precipitate collected by filtration and dried over P2O5 to give pure methyl 2-methyl-3-nitrobenzoate 3 (56 g, 100%) as a white solid: mp. 64.2-65.5° C.; 1H-NMR (CDCl3) δ 8.00 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 3.95 (s, 3H), 2.63 (s, 3H); IR (KBr, cm−1) 1724, 1548, 1279; MS (EI): 195 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.C(O)(C(F)(F)F)=O>C(O)(C)C>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[N:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: O=Cc1cccs1
Reactant: N#Cc1ccsc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: N#Cc1ccsc1N=Cc1cccs1
Yield: 69.4 %

Procedure:
2-Amino-thiophene-3-carbonitrile (50 mg) and thiophene-2-carboxaldehyde (54 mg) were mixed in isopropanol with TFA and refluxed for 20 hours. The reaction was then purified by flash chromatography, resulting in 61 mg (70%) of the title compound as an orange solid. M.p. 58°-60° C. 1H-NMR (300 MHz, [D] acetone): δ=8.49 (s, 1H), 7.90 (d, 1H, 3J=5.0 Hz), 7.82 (dd, 1H, 3J=3.7 Hz and 1.0 Hz), 7.42 (d, 1H, 3J=5.7 Hz), 7.27 (m, 2H, 3J=5.6 Hz). 13C-NMR (300 MHz, [D] acetone): δ=163.4, 155.4, 141.8, 136.2, 133.9, 129.0, 128.1, 122.5, 114.6, 105.8.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](O)=[N:21]4)=[CH:16][CH:15]=3)[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH2:24][C:25]1[C:39]([O:40][CH3:41])=[CH:38][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][C@H:35]([OH:37])[CH3:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:24][C:25]5[C:39]([O:40][CH3:41])=[CH:38][C:28]6[CH2:29][CH2:30][N:31]([CH2:34][C@H:35]([OH:37])[CH3:36])[CH2:32][CH2:33][C:27]=6[CH:26]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:9]=2)(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: O=S(=O)(NC1CC1)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4cccc(S(=O)(=O)NC5CC5)c4)n3n1)CCN(C[C@@H](C)O)CC2

Procedure:
This compound as a yellow solid, was prepared following the same procedure as described for the synthesis of Example 522 by coupling N-Cyclopropyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. MP>150° C. (decomp.). LCMS (E/I+) 563.14 (M+H). 1H NMR (DMSO-d6) δ 9.00 (s, 1H), 8.60 (d, 1H, J=6.50 Hz), 8.20 (s, 1H), 7.95 (s, 1H), 7.85 (m, 2H), 7.70 (t, 1H, J=6.50 Hz), 7.20 (d, 1H, J=6.00 Hz), 7.00 (d, 1H, J=6.00 Hz), 6.80 (s, 1H), 4.30 (broad, 1H), 3.80 (s, 3H), 3.70 (broad, 1H), 2.80 (broad, 2H), 2.70 (broad, 2H), 2.60 (broad, 4H), 2.40 (broad, 2H), 2.10 (broad, 1H), 1.20 (broad, 1H), 1.10 (d, 3H, J=6.00 Hz), 0.50 (broad, 2H), 0.40 (broad, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[S:18]([CH2:24][C:25]#[N:26])([CH2:21][C:22]#[N:23])(=[O:20])=[O:19]>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:21](/[S:18]([CH2:24][C:25]#[N:26])(=[O:20])=[O:19])\[C:22]#[N:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)CC#N
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)CC#N)cc(C(C)(C)C)c1O

Procedure:
M36 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and sulfonyl diacetonitrile under similar conditions as decribed for M27.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([F:15])[CH:8]=2)[N:3]=1.[Mg].S(=O)(=O)(O)[OH:19].[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>ClC(Cl)Cl.S(Cl)(Cl)=O>[Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH2:25][C:24]([O:23][CH2:27][CH3:26])=[O:19])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([F:15])[CH:8]=2)[N:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reaction time: 6 h

Procedure:
A suspension of 38.75 g of 2,7-dichloro-6-fluoroquinoline-3-carboxylic acid in 410 cm3 of trichloromethane and 24 cm3 of thionyl chloride is heated at a temperature close to 60° C., with stirring, for 6 hours. The solution obtained is concentrated to dryness under reduced pressure (20 kPa) at 50° C. The dry extract is twice taken up in a total of 200 cm3 of toluene and again concentrated under reduced pressure under the same conditions as above. The yellow solid obtained, which melts at 124° C., is dissolved in 230 cm3 of anhydrous tetrahydrofuran. The solution obtained is introduced dropwise, with stirring, in the course of 30 minutes, at between 5° and 10° C., into 200 cm3 of a solution of magnesium chelate in tetrahydrofuran, the preparation of which is described below. The temperature is allowed to rise to 20° C. and the mixture is stirred for 1 hour and a half at this temperature. The solution obtained is introduced dropwise, with vigorous stirring, at a temperature close to 5° C., into 1 liter of 0.5 N sulphuric acid. The temperature of the suspension obtained is allowed to rise to 20° C. and the suspension is stirred for a further 2 hours at this temperature. The suspension is extracted with 1 liter of ethyl acetate and the organic and aqueous phases are filtered through diatomaceous silica for filtration, which enables a small amount of insoluble matter to be removed, and the aqueous phase is extracted twice more with 500 cm3 of ethyl acetate. The combined organic extracts are washed with twice 500 cm3 of water, dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 kPa) at 40° C. The residue is taken up in 100 cm3 of diisopropyl ether at 20° C., drained and washed with twice 30 cm3 of diisopropyl ether. 40.55 g of ethyl 3-(2,7-dichloro-6-fluoro-3-quinolyl)-3-oxopropionate are obtained in the form of a beige solid melting at 112°-114° C. This product is used for the subsequent steps without further purification.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]([N:13]([C:19]([O:21][CH2:22][C:23]#[CH:24])=[O:20])[C:14](=[O:18])[C:15](Cl)=[O:16])[C:9]([CH3:12])([CH3:11])[CH3:10].O>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[C:15](=[O:16])[C:14]([N:13]([CH2:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:19]([O:21][CH2:22][C:23]#[CH:24])=[O:20])=[O:18])[CH:2]=[CH2:3]
Reactant: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)Cl
Reactant: C=CCNCC=C
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)N(CC=C)CC=C
Yield: 85.8 %

Procedure:
3.88 g (0.4 mole) of diallylamine are added dropwise to 5.35 g (0.02 mole) of 97% pure N-neopentyl-N-2-propinyloxycarbonyloxamic acid chloride in 50 ml of toluene. During this addition, the internal temperature is kept at 20° C. by external cooling with ice. When the dropwise addition has ended, 30 ml of water are added, the organic phase is separated off and the latter is washed twice with water, dried over sodium sulphate and finally concentrated in vacuo. 5.5 g (86% of theory) of N,N-diallyl-N'-neopentyl-N'-2-propinyloxycarbonyl-oxalic acid diamide of refractive index nD20 =1.4878 are obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13]O)[CH:6]=1>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCc1cccnc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
Thionyl chloride (2.6 g, 22.2 mmol) was added dropwise to a solution of 3-(3-pyridyl)-1-propanol (2.0 g, 14.6 mmol) in chloroform (10 ml) at 0° C. The solution was warmed to 25° C. and stirred 20 hrs. The solution was poured over ice and extracted to ethyl acetate. The organics were combined, dried (MgSO4), and concentrated, to yield 1.68 g of 1-chloro-3-(3-pyridyl)propane hydrochloride (68%) which was used without further purification. Potassium hexamethyldisilazane (0.5 M solution in THF, 1.92 mmol) was added to a solution of (1) (0.39 g, 1.6 mmol) in DMF (5 ml) at 0° C. with potassium iodide (0.16 mmol) and 18-c-6 (0.16 mmol). This mixture was warmed to 25° C. and stirred 1 hr, after which 1-chloro-3-(3pyridyl)propane was added dropwise, and the reaction stirred 20 hrs. The solution was cooled to 0° C., and neutralized with the dropwise addition of saturated NH4Cl (5 ml). The mixture was warmed to 25° C., diluted with saturated NH4Cl, and extracted with ethyl acetate. The organics were combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography (silica gel, 65:36, pentane:ethyl acetate) to yield 0.073 g of product as clear oil (13%). 1H NMR (CDCl3): δ 0.86 (t, 3H); 1.28 (2 overlapping s's, 6H); 1.71 (m, 2H); 1.98 (overlaping m's, 5H); 2.59 (t, 2H); 2.73 (m, 1H); 3.38 (m, 1H); 3.75 (m, 2H); 3.89 (m, 2H); 7.21 (m, 1H); 7.49 (m, 1H); 8.45 (m, 2H).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17](CC#N)([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1.[OH-:25].[K+].[CH2:27]([OH:30])[CH2:28]O>>[OH:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:28][C:27]([OH:30])=[O:25])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1
Reactant: N#CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Reactant: [OH-]
Reactant: OCCO
Agent: [K+]
Product: O=C(O)CC12CCC(c3cccc(O)c3)(CC1)OC2
Temperature: 165 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 4-(iodomethyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octane (1.5 g, 3.50 mmol) and NaCN (0.687 g, 14.01 mmol) in DMF (8 mL) was stirred at 80° C. for 18 h. The reaction was diluted with EtOAc (10 mL), washed with water (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetonitrile (1.15 g, 3.50 mmol, 100% yield) as light brown oil. The above nitrile (1.15 g, 3.50 mmol) was taken up in ethylene glycol (20 mL) and treated with 40% KOH (5.00 mL, 35.0 mmol). The reaction was stirred at 165° C. for 18 h and concentrated in vacuo. The residue was dissolved in water (15 mL), acidified to pH 2 with 1 N aqueous HCl, and extracted with EtOAc (5×5 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to afford the title compound (0.91 g, 99% yield) as a light brown solid. LCMS, [M−H]+=261.3.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[C:4](=[O:18])[N:3]1[CH2:19][C:20]([OH:22])=[O:21].S(=O)(=O)(O)O.[C:28](=O)(O)[O-].[Na+]>CO>[CH3:28][O:21][C:20](=[O:22])[CH2:19][N:3]1[C:4](=[O:18])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)[C:2]1=[O:1]
Reactant: O=C([O-])O
Reactant: O=C(O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Reaction time: 18 h

Procedure:
A mixture of 20 ml of methanol, 6.27 g of (1,3-dioxo-5-phenylsulfanyl-1,3-dihydro-isoindol-2-yl)-acetic acid (20 mmol) and 0.3 ml of concentrated sulfuric acid was refluxed with stirring for 18 h. Then 100 ml of concentrated aqueous sodium bicarbonate solution were added and the mixture was extracted with 100 ml of ethyl acetate. The organic phase was dried over MgSO4 and evaporated in vacuo. 6.54 g of the title compound were obtained; MS-(+)-ion: M+1=328.0.
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.P(Cl)(Cl)([Cl:22])=O>C(#N)C.O1CCOCC1>[Cl:22][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1

Procedure:
4-(4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile (2.36 g, 0.01 mol) are suspended in 40 ml acetonitril and 4.99 ml (0.02 mol) 4 N hydrochloric acid solution in dioxane. After addition of 3.66 ml (0.04 mol) phosphorus oxichloride the mixture is heated under reflux for 3 days. The solid is filtered off and the mother liquor evaporated. The residue and the solid are dissolved in 30 ml DMF at 60° C. and 25 ml of a conc. sodium bicarbonate solution and 25 ml water are added and the resulting suspension cooled, filtered and the solid washed with water. The title compound is dried at 100° C. for 6 h under reduced pressure; m.p. 296-297° C.; HPLC tR=11.59 min.
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[N:12]3[C:16]4=[C:17]5[CH:23]=[CH:22][NH:21][C:18]5=[N:19][CH:20]=[C:15]4[NH:14][C:13]3=[O:24])[CH2:3]1)[CH2:9]2.C(S(F)(F)([F:31])(CC)N)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl>[F:31][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[N:12]3[C:16]4=[C:17]5[CH:23]=[CH:22][NH:21][C:18]5=[N:19][CH:20]=[C:15]4[NH:14][C:13]3=[O:24])[CH2:3]1)[CH2:9]2
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1C1C2CC3CC1CC(O)(C3)C2
Reactant: CCS(N)(F)(F)(F)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cnc3[nH]ccc3c2n1C1C2CC3CC1CC(F)(C3)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(5-Hydroxyadamantan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (92 mg) was suspended in dichloromethane, and diethyl aminosulfur trifluoride (DAST) was added. The mixture was stirred at ambient temperature for 1 hour. The saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The obtained solid was collected by filtration and washed with diisopropyl ethylether to obtain (5-fluoroadamantan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (34 mg).