Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A suspension of 4-chloro-6,7-dimethoxyquinoline (1566 mg, 7.00 mmol), 4-aminophenol (917 mg, 8.40 mmol) and cesium carbonate (4561 mg, 14.0 mmol) in dimethyl sulfoxide (14 ml) was stirred at 100° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran (=1/1). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate/methanol=60/40). Ethyl acetate was added to the obtained residue and the mixture was filtrated to give the title compound (1267 mg, 61%) as a white powder.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([O:31]C)=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccnc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccnc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidinecarboxylate (430 mg, 0.94 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 235 mg (57%) of the acid. HR-MS: m/z Calculated for C22H22N2O6S 443.1271; Found 443.1270.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][F:22])[C:17](O)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][F:22])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CCF)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CCF)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
100 mg (274 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoic acid (racemate), 53.0 mg (274 μmol) of tert-butyl 4-aminobenzoate, 39.0 mg (274 μmol) of Oxima and 43.0 μl (274 μmol) of DIC in 5 ml of dimethylformamide were reacted according to General Method 5B. Filtration gave the title compound. Yield: 117 mg (78% of theory)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][C:4]2[NH:18][CH:19]=[CH:20][C:3]1=2.[NH:21]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:36]=O>>[CH2:29]([N:21]([CH2:36][C:20]1[C:3]2[C:2](=[O:1])[NH:7][C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][C:4]=2[NH:18][CH:19]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCCCCC(=O)Nc1nc2[nH]ccc2c(=O)[nH]1
Reactant: C=O
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: CCCCCCCC(=O)Nc1nc2[nH]cc(CN(Cc3ccccc3)Cc3ccccc3)c2c(=O)[nH]1

Procedure:
The syntheses of 4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoic acid 21 and 2-amino-5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 24 are shown in FIG. 22. FIG. 22A details the synthesis of 4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoic acid 21. 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 15 is reacted with octanoyl chloride in pyridine to produce octanoic acid(7-octanoyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 16, which is then treated with ammonia in methanol to produce octanoic acid(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 17. Octanoic acid(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 17 is reacted with (PhCH2)2NH in formaldehyde to produce octanoic acid{5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide 18. Octanoic acid{5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide 18 is reacted with 4-amino-methylbenzoate 19 to yield 4-[(2-octanoylamino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoic acid methyl ester 20. Treatment of 4-[(2-octanoylamino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoic acid methyl ester 20 with 5 M KOH in ethanol yields 4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoic acid 21.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH2:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)nc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 68.2 %

Procedure:
A mixture of methyl 6-chloronicotinate (8.0 g), (3R)-(−)-1-benzyl-3-aminopyrrolidine (9.86 g), CuO (371 mg) and K2CO3 (8.38 g) in DMF (60 ml) was stirred at 100° C. for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (97:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}nicotinate (9.9 g).
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[C:4]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:22](OCC)[CH3:23].C1(N)CC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:21]1([N:2]2[C:12]3[C:11](=[CH:16][C:15]([F:17])=[C:14]([F:18])[CH:13]=3)[C:10](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Reactant: CCOCC
Agent: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of ethyl 3-(dimethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (Example 48a) (75 g, 249 mmol) in a mixture of Ethanol (100 mL)/Diethyl ether (200 mL) was added to cyclopropanamine (34.5 mL, 498 mmol). After 2 h of stirring at rt, LCMS showed complete disappearance of starting material. The reaction mixture was evaporated under reduced pressure, the oily residue was dissolved in N,N-Dimethylformamide (DMF) (250 mL) and potassium carbonate (103 g, 747 mmol) was then added. The reaction mixture was stirred at 100° C. for 2 h, and LCMS showed completion of reaction. Cold water was added to the mixture. The precipitates were collected by filtration and dried to afford ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (71 g, 242 mmol, 97% yield) as a pale yellow solid. LCMS: [M+H]+: 294.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 111.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.7 mg, 0.0504 mmol) was dissolved in acetonitrile (1 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (28 mg, 0.22 mmol), acetic acid (0.232 mL, 4.05 mmol) and sodium triacetoxyborohydride (116 mg, 0.547 mmol). The reaction mixture was added with water and sodium carbonate, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indol-2-yl)isoindolinone (29.6 mg).
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13]([OH:15])=O)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:18]([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:27]2[CH2:35][C@@H:24]1[CH2:25][CH2:26]2)=[O:22])[CH3:19].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:18]([O:20][C:21]([C@H:23]1[C@@H:28]([N:29]([C:13](=[O:15])[CH2:12][C:7]2[NH:6][C:5]3[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=3[S:9](=[O:10])(=[O:11])[N:8]=2)[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:27]2[CH2:35][C@@H:24]1[CH2:25][CH2:26]2)=[O:22])[CH3:19]
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852, 0.2 g, 0.546 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (1S,2R,3S,4R)-3-(3-Methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 22a, 0.138 g, 0.546 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.573 mmol). Then N-methylmorpholine (0.116 g, 1.15 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 16 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C24H321N3O5S 601.11, found 602.6 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:31]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:31][CH2:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CC(=O)c1cnc(C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(C(=O)CBr)cn1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a chloroform (28 mL) solution of 1-(5-methylpyrazin-2-yl)ethanone (1.9 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (2.7 mL) and trimethylsilyl trifluoromethanesulfonate (3.0 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (3.0 g) was added thereto, and the resultant was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the resultant was stirred for 15 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→60/40) and then further purified by hexane/ethyl acetate-gradient elution (=90/10→80/20) to obtain the title compound (2.1 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8]C1C=CC=C(C(OO)=[O:16])C=1.C(OCC)C.Cl>CC(C)=O>[ClH:8].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: Nc1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of amino pyridine (50 g, 0.53 mol) in acetone (900 OmL) a solution of 3-chloro perbenzoic acid (112.2 g, 0.65 mol) in acetone (300 mL) was added and the reaction mixture stirred at room temperature for 30 min. Diethyl ether (500 mL) was added and the solution acidified to pH 4 with concentrated HCl. The amino pyridine-N-oxide hydrochloride salt was then isolated by filtration as an off-white powder (62 g, 80%); m/z (ES+) 111; 1H NMR (d6 DMSO) d 8.14 (dd, J=6.9, 1.8 Hz, 1H), 7.66 (s, 2H, NH2), 7.47 (dt, J=7.6, 1.5 Hz, 1H), 6.99 (dd, J=8.1, 1.5 Hz, 1H), 6.72 (dt, J=7.6, 1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1.[C:40]1([C:46]2([C:52]([OH:54])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(OCC)(=O)C.ClCCl>CO.ClCCl>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:22][CH2:23][N:49]3[CH2:48][CH2:47][C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:52]([OH:54])=[O:53])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: O=C(c1ccccc1)N1CC[C@@](CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Agent: CN1CCN(C(N)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1)N1CC[C@](CCN2CCC(C(=O)O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid 4-methylpiperazine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with ethyl acetate, dichloromethane, 2% methanol/dichloromethane, 4% methanol/dichloromethane, 6% methanol/dichloromethane, and then 8% methanol/dichloromethane, the title compound: Rf =0.27 (silica gel, methanol/dichloromethane 1/9).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([C:21]([CH2:23][CH2:24][CH2:25]Cl)=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:25][CH2:24][CH2:23][C:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:22])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: O=C(CCCCl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl benzyl ketone (2.9 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography [Kieselgel 60, eluant: benzene-ether (10:1)] to obtain 1-methyl-5-[3-(benzylcabonyl)propyl]thio-1,2,3,4-tetrazole (yield 50%) as colorless liquid, nD25 =1.5610.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1.N12CCCN=C1CCCCC2>C(#N)C>[OH:18][CH:19]1[CH2:20][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[N:36]=[CH:35][NH:34][C:33]4=[N:37][CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:22]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC1(n2cc(-c3nc[nH]c4nccc3-4)cn2)CC(O)C1
Temperature: 50 °C

Procedure:
(3-[tert-Butyl(diphenyl)silyl]oxycyclobutylidene)acetonitrile (0.15 g, 0.00043 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.14 g, 0.00043 mol) in acetonitrile (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL, 0.00043 mol) was added under nitrogen. The mixture was heated to 50° C. over night. LCMS showed a peak with m/z of 425.4, indicating a de-silyl reaction occurred simultaneously during the Micheal addition. The reaction was concentrated and purified on combiflash (silica gel, 0-100% EtOAc/Hex) to yield the desired produt. LCMS (M+H) 425.4.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[F:17])=[C:5]([C@@H:18]2[CH2:22][CH2:21][CH2:20][C:19]2([CH3:24])[CH3:23])[CH:4]=1.ClC[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37](OC)[CH:36]=[CH:35][C:34]=2F)=[C:29]([C@H]2CCCC2(C)C)[CH:28]=1.CC1(C)CCC[C@H]1C1C=C(CO)C=CC=1C1C=C(OC)C=CC=1F.CC1(C)CCC[C@@H]1C1C=C(CO)C=CC=1C1C=C(OC)C=CC=1F.C(Cl)Cl.S(Cl)(Cl)=O>CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[F:17])=[C:5]([C@@H:18]2[CH2:22][CH2:21][CH2:20][C:19]2([CH3:24])[CH3:23])[CH:4]=1.[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(F)c(-c2ccc(CCl)cc2[C@H]2CCCC2(C)C)c1
Agent: COc1ccc(F)c(-c2ccc(CCl)cc2[C@@H]2CCCC2(C)C)c1
Agent: COc1ccc(F)c(-c2ccc(CO)cc2[C@@H]2CCCC2(C)C)c1
Agent: COc1ccc(F)c(-c2ccc(CO)cc2[C@H]2CCCC2(C)C)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 92 %

Procedure:
4-(Chloromethyl)-2-((1R)-2,2-dimethylcyclopentyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl or 4-(chloromethyl)-2-((1S)-2,2-dimethylcyclopentyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl (66.6O or 66.6P). To a stirred solution of (2-((1R)-2,2-dimethylcyclopentyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methanol or (2-((1S)-2,2-dimethylcyclopentyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methanol (66.6AG or 66.6AH) (23.66 g, 72 mmol) in DCM (360 mL, 72 mmol) and DMF (0.56 mL, 7.2 mmol) at 0° C. was added thionyl chloride (11 mL, 144 mmol). Stirring was continued at room temperature for 1 hour. The reaction as then concentrated in vacuo, and the residue was purified on silica gel (0-10% EtOAc in hexanes) to yield 66.6O or 66.6P as a colorless oil (23.0 g, 92% yield). MS ESI (pos.) m/e: 364.1 (M+H2O)+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC>N1C=CC=CC=1.CCOCC.[Cu].[Cu]I>[N:14]1([C@@H:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([N:24]5[C:25](=[O:28])[CH:26]=[CH:27][N:22]=[CH:23]5)[CH:21]=[CH:20][C:5]=4[N:6]=3)[CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: O=c1ccnc[nH]1
Agent: [Cu]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=c1ccncn1-c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1

Procedure:
A solution of (R)-6-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 14, 80 mg, 0.218 mmol), pyrimidin-4(3H)-one (31.5 mg, 0.328 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (31.1 mg, 0.218 mmol), copper (27.8 mg, 0.437 mmol) and copper(I) iodide (8.32 mg, 0.044 mmol) in pyridine (3 ml) was heated in a microwave reactor to 200° C. for 30 minutes. The mixture was diluted with ether (20 mL) and washed with water, a small amount of aqueous NH4OH and brine. The organic layer was separated and dried with MgSO4 and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel column eluting with 3% (9:1 methanol:concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43-1.52 (m, 2H), 1.58-1.69 (m, 4H), 1.94-2.11 (m, 1H), 2.25-2.37 (m, 1H), 2.39-2.58 (m, 4H), 2.96-3.09 (m, 1H), 3.40-3.63 (m, 2H), 3.72-3.92 (m, 2H), 6.56 (d, J=6.74 Hz, 1H), 7.22 (dd, J=8.72, 2.38 Hz, 1H), 7.62 (d, J=2.38 Hz, 1H), 7.65 (d, J=8.33 Hz, 1H), 7.94 (d, J=6.74 Hz, 1H), 8.20 (s, 1H); MS (DCI/NH3) m/z 382 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([NH:19][C:20]3[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][C:34](=O)[C:35](O)=[O:36])[CH:28]=1>C(O)C>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][C:34]2[C:35](=[O:36])[N:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13](/[CH:12]=[CH:11]/[C:8]4[CH:9]=[N:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=4)[CH:14]=3)[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:26]=2)[CH:28]=1
Reactant: O=C(O)C(=O)Cc1cccnc1
Reactant: CC(=O)Nc1ccc(/C=C/c2cccc(Nc3ncccc3N)c2)cn1
Solvent: CCO
Product: CC(=O)Nc1ccc(/C=C/c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)cn1
Yield: 85.4 %

Procedure:
A suspension of 2-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenylamino]-3-aminopyridine (1.5 g) and 3-pyridylpyruvic acid (0.79 g) in ethanol (30 ml) was stirred under reflux for 8 hours. The cold reaction mixture was filtered and washed with ethanol to give 2-(3-pyridylmethyl)-3-oxo-4-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine as colorless crystals (1.76 g).