Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12.[Br-].[Li+]>>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Br-]
Agent: [Li+]
Product: O=C1CCCCCCCCCCC1
Yield: 96.6 %

Procedure:
Further, Zh. Org. Khim (1990), 26(7), 1497-1500, discloses that, when an isomerization reaction of an epoxycyclododecane was carried out in the presence of 2.3 molar % of a catalyst consisting of LiBr (lithium bromide) at a reaction temperature of 150° C. for a reaction time of 10 hours, the target cyclododecanone was obtained at a yield of 96.6%, and when the reaction of the epoxycyclododecane was effected in the presence of 1.5 molar % of LiI (lithium iodide) at 150° C. for 5 hours, the target cyclododecanone was obtained at a yield of 91.2%. In the case of this report, however, it is assumed that, to make the conversion of the epoxycyclododecane close to 100%, a very long reaction time is necessary. Also, the reaction of the report was effected in a batch-type reaction system, and thus no continuous method for the reaction is disclosed in the report.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=1)[OH:14])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:52]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([N:8]([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=1)[OH:14])[CH2:9][CH2:10][Br:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cccc([C@@H](O)CN(CCO)Cc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccccc1)c1cccc([C@@H](O)CN(CCBr)Cc2ccccc2)c1
Temperature: -20 °C

Procedure:
(R)-2-[N′-Benzyl-N′-(2-hydroxyethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol (173 mg; synthesized according to the process described in WO 01/04092) and triphenylphosphine (103 mg) were dissolved in dehydrated methylene chloride (5 mL), followed by stirring at −20° C. N-Bromosuccinimide (69.9 mg) was added at a stretch and the resulting mixture was stirred for 10 minutes. The reaction mixture was purified by silica gel column chromatography (5:1-3:1 hexane/ethyl acetate) to yield (R)-2-[N′-benzyl-N′-(2-bromoethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol. This was immediately dissolved in acetonitrile (2.5 mL). The compound (79.8 mg; obtained in the above step B) and an aqueous 1 N sodium hydroxide solution (392 μL) were added, followed by stirring at room temperature for 14 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (4:1-2:1 hexane/ethyl acetate) to yield the title compound (132.2 mg).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCc3ccccn3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCc3ccccn3)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A mixture of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (5.45 g), conc. hydrochloric acid (5 ml) and methanol (150 ml) was stirred at ambient temperature for 1.5 hours. After removal of the solvent, to the residue were added ethyl acetate and water, followed by adjusting to pH 7 with 20% aqueous sodium carbonate. The separated ethyl acetate solution was washed with an aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.6 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:27][CH3:28])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:10]1)(=O)[CH3:7].[C:29]([C:31]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:32]=1[NH2:33])#[N:30].[OH-].[Na+]>C(Cl)Cl.O>[CH2:20]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:27][CH3:28])[CH2:10][N:9]([C:6](=[N:33][C:32]1[CH:34]=[C:35]([O:40][CH3:41])[C:36]([O:38][CH3:39])=[CH:37][C:31]=1[C:29]#[N:30])[CH3:7])[CH2:18][CH2:17]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN(C(C)=O)C2
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(C#N)c(N=C(C)N2CCc3cc(OCc4ccccc4)c(OC)cc3C2)cc1OC
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Phosphorus oxychloride (3.24 ml) was added over 1 minute to a stirred solution of N-acetyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (10 g) in methylene chloride (100 ml) at 10°. After stirring for twenty minutes at room temperature, a solution of 2-cyano-4,5-dimethoxyaniline (5.72 g) in methylene chloride (80 ml) was added and the resulting suspension was heated at reflux for 16 hours. The reaction mixture was then allowed to cool, water (60 ml) was added followed by 40% sodium hydroxide to pH 8-9 with stirring for five minutes. The organic layer was then separated and the aqueous phase extracted with methylene chloride (3×50 ml). The combined organic layers were washed (H2O), dried (MgSO4) and evaporated. The residue was chromatographed on silica (Merck Art.9385) under medium pressure, eluting with methylene chloride containing gradually increasing amounts of methanol (0-10%). Some impure product-containing fractions were re-chromatographed on silica but using methylene chloride containing 2-4% methanol. The pure product-containing fractions were combined, evaporated, and the residue recrystallised from ethyl acetate to give the title compound as a colourless powder (11.02 g), m.p. 164°-5° (d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:8]O.[Cl:10]NC(=O)CCC(N)=O>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:10])=[NH:8]
Reactant: ON=Cc1ccccn1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CN(C)C=O
Product: N=C(Cl)c1ccccn1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a mixture of pyridin-2-carbaldehyde-oxime (15 gm) and N-chlorosuccinamide (25 gm) in DMF (30 ml) was stirred at 30° C. over a period of 2 h. The reaction mixture was quenched with ice cold water (150 ml). The suspension was filtered and the wet cake washed with small quantity of water to provide pure title compound in 7 gm quantity (55%) as a white solid.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[C:31]#[CH:32])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>ClCCl.CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[C:31]#[C:32][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: CC1CCN(Cc2ccc(I)cc2)CC1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)4-methylpiperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 50 mg (27% of theory); C28H27ClN2O (M=442.99); calc.: molecular ion peak (M+H)+: 443/445; found: molecular ion peak (M+H)+: 443/445; Rf value: 0.45 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: FC1C=CC(C(O)=O)=C(OCCC(N=C=O)OC(C)(C)C)C=1.[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([O:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:25]=1>>[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([O:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:25]=1
Reactant: COC(=O)c1ccc(F)cc1OCCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(CCOc1cc(F)ccc1C(=O)O)N=C=O
Product: CC(C)(C)OC(=O)NCCCOc1cc(F)ccc1C(=O)O

Procedure:
Using a procedure analogous to Example 21-D, 4-fluoro-2-(3-tert-butoxy-carbonylaminopropoxy)benzoic acid was prepared from methyl 4-fluoro-2-(3-tert-butoxycarbonylaminopropoxy)benzoate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH2:22][C:23](O)=[O:24])([CH3:9])[CH3:8].[S:26](=[O:50])(=[O:49])([O:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][C:32]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[CH:31][C:30]=1[CH:46]([CH3:48])[CH3:47])[NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][C:32]1[CH:31]=[C:30]([CH:46]([CH3:48])[CH3:47])[C:29]([O:28][S:26](=[O:50])(=[O:49])[NH:27][C:23](=[O:24])[CH2:22][C:11]2[C:10]([CH:7]([CH3:8])[CH3:9])=[CH:15][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:13][C:12]=2[CH:19]([CH3:21])[CH3:20])=[C:34]([CH:35]([CH3:37])[CH3:36])[CH:33]=1)([CH3:43])([CH3:45])[CH3:44]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(C)C)c1OS(N)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(C)C)c(C(C)C)c1
Reaction time: 6 h
Yield: 72.2 %

Procedure:
Oxalyl chloride (2.45 mL, 28 mmol) was added dropwise to a solution of 2,4,6-triisopropylphenyl acetic acid (5.66 g, 21.6 mmol) in 150 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred for 6 hours and then concentrated in vacuo. The residue was redissolved in 150 mL dichloromethane. 4-(Tert-butyl-dimethyl-silanyloxy)-2,6-diisopropylphenyl sulfamate (8.36 g, 21.6 mmol) and triethylamine (7.5 mL, 54 mmol) were added, and the resulting mixture was stirred overnight. Washed with 1M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give 9.86 g of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-(tert-butyl-dimethyl-silanyloxy)-2,6-diisopropyl-phenyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[NH2:26][C:27]1[N:28]=[CH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].CCOC(C)=O>[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[C:27]([NH:26][C:2]2[CH:7]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)[N:28]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: O=C(COCc1ccccc1)N1CCN(Cc2ccnc(Cl)c2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(COCc1ccccc1)N1CCN(Cc2ccnc(Nc3cc4ccccc4cn3)c2)CC1

Procedure:
1-(2-Chloropyridin-4-ylmethyl)-4-benzyloxyacetylpiperazine (1.0 equiv) (Preparation B-16) was mixed with 3-aminoisoquinoline (1.0 equiv), Pd2(dba)3(0.1 equiv), xantphos (0.15 equiv), and Cs2CO3 (1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[Li]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:13]1[S:12][CH:16]=[CH:15][N:14]=1)([OH:11])[CH3:10]
Reactant: [Li]c1nccs1
Reactant: CC(=O)c1cc(Br)ccc1N
Product: CC(O)(c1nccs1)c1cc(Br)ccc1N

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl)-ethanone and 2-thiazolyl lithium generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 7.70 (d, J=3.3 Hz, 1H), 7.64 (d, J=3.2 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.5, 2.4 Hz, 1H), 6.92 (s, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.50 (s, 2H), 1.90 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[Cs+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1I
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1

Procedure:
A solution of 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202; 200 mg; 0.55 mmol), phenylboronic acid (68 mg; 0.55 mmol;) was placed in a microwave vial and treated with caesium fluoride (252 mg; 1.66 mmol) and bis(triphenylphosphine)palladium(II) chloride (39 mg; 0.06 mmol). The tube was sealed and degased with N2 before adding dioxane (3 ml) and water (1.5 ml). The resulting reaction mixture was irradiated in a microwave reactor at 110° C. for 20 minutes. The reaction mixture was taken up in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc affording the title compound as an orange sticky solid.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[N:8]=[CH:7][C:6]=1[C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:23]1)=[O:21])[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:1]([S:4][C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)[N:8]=[CH:7][C:6]=1[C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:34])([F:35])[F:36])[CH2:23]1)=[O:21])[CH2:2][CH3:3]
Reactant: CCCSc1c(C(=O)N2CCC(c3ccccc3C(F)(F)F)C2)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)N2CCC(c3ccccc3C(F)(F)F)C2)cnn1-c1ccc(C(=O)O)cc1
Yield: 67.8 %

Procedure:
Methyl 4-[5-propylsulfanyl-4-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl]pyrazol-1-yl]benzoate (Intermediate #6) (177 mg, 0.34 mmol) was stirred at ambient temperature for 18 h in a mixture of methanol (5 mL) and 2M sodium hydroxide (0.855 mL, 1.71 mmol) for 18 h. The reaction mixture was evaporated to remove the methanol. The residue was dissolved in water (20 mL) and acidified to pH4 with 2M HCl. The resulting white precipitate was recovered by filtration, washed with water and dried under vacuum to give the title compound as a white solid (116 mg, 68%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:14]2[N:15]=[CH:16][N:17]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:8]1([C:14]2[N:15]=[CH:16][N:17]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccc3)c2-c2ccncn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ncn(C3CCNCC3)c2-c2ccncn2)cc1
Reaction time: 2 h
Yield: 52.3 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 4-(4-phenyl-5-pyrimidin-4-yl-1H-imidazol-1-yl)piperidine-1-carboxylate (C22) (267 mg, 0.658 mmol) in dichloromethane (5 mL). After 2 hours, the reaction was concentrated in vacuo, and then treated with saturated aqueous sodium bicarbonate solution. The mixture was extracted with warm ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting light yellow oil solidified over the course of several days to provide 105 mg of product that was contaminated with approximately 20% of a related impurity. Fine white needles precipitated out of the aqueous layer; these were collected by filtration to provide additional product as a cream colored solid. Yield from aqueous layer: 54 mg, 0.18 mmol, 27%. 1H NMR (400 MHz, CDCl3) δ 1.83-1.93 (m, 2H), 2.12-2.18 (m, 2H), 2.72 (ddd, J=12.3, 12.3, 2.3 Hz, 2H), 3.20-3.25 (m, 2H), 4.85 (tt, J=12.0, 4.0 Hz, 1H), 7.19 (dd, J=5.3, 1.5 Hz, 1H), 7.30-7.36 (m, 3H), 7.42-7.45 (m, 2H), 7.85 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:25]=[C:24]([O:26]CC)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH2:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc12
Agent: Cl
Product: O=C1CC(NCCCOc2cccc(CN3CCCCC3)c2)=Nc2ccccc21

Procedure:
2-[3-[3-(Piperidinomethyl)phenoxy]propylamino]-4-ethoxyquinoline (liberated from the dimaleate (3.0 g)) was stirred under reflux in concentrated hydrochloric acid (30 ml) for 41/2 hours. The reaction mixture was cooled, reduced in volume by evaporation under reduced pressure, taken to pH 9 (aqueous NaHCO3), washed with ether, and extracted into chloroform (3×). The chloroform extracts were combined, dried (MgSO4), evaporated under reduced pressure and the resultant white oil was treated with hot ethylacetate to give the title compound (0.89 g), m.p. 171°-171.5° C. (recrystallised from methanol).
Reaction SMILES: [CH2:1]1[C@H:13]2[C@H:4]([N:5]([CH2:14][CH2:15][NH2:16])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:3][CH2:2]1.C=O.[C:19](O)(C(F)(F)F)=O>CCO>[CH2:14]1[N:5]2[C:6]3[C:11]([CH2:12][C@@H:13]4[CH2:1][CH2:2][CH2:3][C@H:4]42)=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:19][NH:16][CH2:15]1
Reactant: NCCN1c2ccccc2C[C@H]2CCC[C@H]21
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: CCO
Product: c1cc2c3c(c1)C[C@@H]1CCC[C@H]1N3CCNC2

Procedure:
A flask containing Cis 2-(1,2,3,3a,9,9a-Hexahydro-cyclopenta[b]quinolin-4-yl)-ethylamine (0.18 g, 0.84 mmol) and 0.07 ml of 37% aqueous formaldehyde in 2 ml of EtOH was treated with TFA (0.07 mL, 0.92 mmol) at room temperature for 1 hr. The mixture was concentrated under reduced pressure, and the residue was taken up in dichloromethane, washed with 1 N NaOH (15 mL), Brine (15 mL) and then dried with MgSO4. Evaporation and flash chromatography (10% 2N NH3 in ethanol/dichloromethane) afforded the title compound, which was converted to the HCl salt to give a brown solid (0.19 mg, 85%): The same step 5 procedure was used to prepare the trans isomer except that Trans 2-(1,2,3,3a,9,9a-Hexahydro-cyclopenta[b]quinolin-4-yl)-ethylamine was used instead of the cis isomer.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]([CH2:17][CH3:18])[C:7]2=[O:19].[CH3:20][C@@H:21]1[C:25]2[NH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:24]=2[C:23](=[O:38])[NH:22]1>>[C:13]([NH:12][C:9]1[N:8]([CH2:17][CH3:18])[C:7](=[O:19])[C:6]2[C:11](=[C:2]([C:27]3[NH:26][C:25]4[C@@H:21]([CH3:20])[NH:22][C:23](=[O:38])[C:24]=4[CH:28]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CCn1c(NC(C)(C)C)nc2c(Br)cccc2c1=O
Product: CCn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](C)NC4=O)cccc2c1=O
Yield: 14.5 %

Procedure:
This compound (8.8 mg, 11% yield) as an off-white solid was prepared according to the procedure given in 405, using 8-bromo-3-ethylquinazoline-2,4(1H,3H)-dione (52 mg, 0.160 mmol, 481d) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (84 mg, 0.321 mmol, 705) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 12.41 (1H, br. s.) 8.02 (1H, d, J=8.41 Hz) 8.06 (1H, d, J=8.61 Hz) 7.23 (1H, br. s.) 6.84 (1H, s) 5.61 (1H, br. s.) 4.66 (1H, br. s.) 4.16 (1H, d, J=7.04 Hz) 3.50 (2H, s) 1.67 (9H, s) 1.54 (3H, d, J=6.46 Hz) 1.40 (3H, t, J=6.85 Hz). m/z (ESI, +ve) 380.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N-:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[N-]S(=O)(=O)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
4-Bromo-N-(tert-butyl)benzenesulfonyl amide (100 mg, 0.342 mmol) and potassium carbonate (95 mg, 0.684 mmol) were dissolved in DMF (2 ml), followed by addition of iodomethane (0.043 ml, 0.684 mmol), and then the resulting liquid was stirred at room temperature for 18 hours. Distilled water (10 ml) was added to the resulting reaction liquid, followed by extraction with EtOAc (10 ml×3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 77 mg of yellow oil (73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=O)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CO.CN1C(=O)N(C)CCC1.C(O)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: C1COCCN1
Agent: [Ni]
Solvent: CN1CCCN(C)C1=O
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]c(CN4CCOCC4)cc23)c1

Procedure:
109 mg (0.40 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage 1.6) and 70 μl (0.8 mmol) of morpholine in 6 ml of methanol, 2 ml of DMPU and 50 μl of acetic acid are heated at 50° C. for 2 h. 30 mg of Raney nickel are then added and the mixture is hydrogenated at 50° C. The catalyst is filtered off, the filtrate is evaporated and the residue is dissolved in ethyl acetate and satd Na2CO3 solution. The aqueous phase separated off is extracted twice with ethyl acetate; the organic phases are washed with satd NaHCO3 solution, twice with water and brine, dried (MgSO4) and evaporated. The residue is taken up in methanol, and the solution is treated with silica gel and dried. The powder is added to a silica gel column and eluted with CH2Cl2/methanol=10:1. Crystallization from ethyl acetate/diethyl ether/hexane yields 4-(3-chloroanilino)-6-[(morpholin-4-yl)-methyl]-7H-pyrrolo[2,3-d]pyrimidine; m.p: 244-246° C.; HPLC: tRet(Grad20)=7.4; TLC-Rf=0.20 (CH2Cl2/methanol 10:1); FAB-MS: (M+H)+=344.