Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[CH:12]([OH:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])(=O)=O>C1(C)C=CC=CC=1>[Si:53]([O:36][CH:12]1[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]2[N:7]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]1=2)([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O)C1
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
0.529 g (1 mmol) of [2-cyclopentyl-4-(3,4-difluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-3-yl]-(4-trifluoromethylphenyl)-methanone are dissolved in 6 ml of abs. toluene and admixed with 0.465 ml of lutidine at −5° C. At from −5° C. to −10° C., 0.459 ml (2 mmol) of tert-butyldimethylsilyl trifluoromethanesulphonate is added. The mixture is stirred at 20° C. for 3 hours. The mixture is diluted with toluene, the reaction is quenched with 10% strength aqueous ammonium chloride solution and the organic phase is washed with 0.1 N hydrochloric acid and saturated aqueous sodium bicarbonate solution and dried. The solvent is distilled off under reduced pressure and the residue is then purified using a column. This gives 620 mg of colourless crystals of melting point: 128° C.-129° C.
Reaction SMILES: [C:1]([CH:9](Br)[CH2:10][CH2:11][Cl:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][C:16](=[S:18])[S-:17].C[NH3+]>>[CH3:14][N:15]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]([CH2:10][CH2:11][Cl:12])[S:18][C:16]1=[S:17]
Reactant: O=C(c1ccccc1)C(Br)CCCl
Reactant: CNC(=S)[S-]
Agent: C[NH3+]
Product: Cn1c(-c2ccccc2)c(CCCl)sc1=S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 3-methyl-4-phenyl-5-β-chloroethyl-4-thiazoline-2-thione is prepared in the following manner: A solution of 33 g of 1-benzoyl-1-bromo-3-chloropropane in 150 cc of absolute alcohol is added slowly to a suspension of 20 g of methyl ammonium N-methyldithiocarbamate in 150 cc of absolute alcohol. The mixture is agitated for 2 hours at ambient temperature and the solvent is then evaporated under reduced pressure. The residue is redissolved in chloroform, washed with water and the separated organic phase is dried over Na2SO4 and then evaporated to dryness.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.O1CCCC1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH2:30][C:31]#[CH:32])=[CH:24][CH:23]=1>O.CN(C)C=O>[CH2:30]([O:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:27][CH:26]=1)[C:31]#[CH:32]
Reactant: C#CCOCc1ccc(CCl)cc1
Reactant: Nc1ncccc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCc1ccc(Cn2cc(-c3cccnc3N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a mixture of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (30 mg, 0.19 mmol) described in Manufacturing Example 32-1-4 and tetrahydrofuran (1 mL) was added sodium hydride (12 mg, 0.24 mmol, 50% in oil) at 0° C., and then N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 10 minutes at room temperature, after which 1-chloromethyl-4-prop-2-ynyloxymethyl-benzene (47 mg, 0.24 mmol) described in Manufacturing Example 194-1-2 was added to this mixture at 0° C., which was stirred for 2 hours at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1) to obtain the title compound (37 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[N:4][C:5]([C:8]([NH2:10])=O)=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[N:4][C:5]([C:8](=[S:29])[NH2:10])=[N:6][CH:7]=1
Reactant: NC(=O)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=S)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carboxamide (500 mg, 1.79 mmol) and Lawesson's reagent (1.45 g, 3.58 mmol, 2.0 eq) in toluene (30 ml) and THF (20 ml) was stirred at 50° C. for 17 h, and then, concentrated. The residue was recrystallized with toluene to give the crude 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbothioamide (2.3 g, directly used for the next step). LC-MS (m/z)=295.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])[C:13]1=[O:29]>O.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[C:13]1=[O:29]
Reactant: CCOC(=O)C(C(=O)OCC)c1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(CC(=O)O)c1=O
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 9.9 %

Procedure:
The crude product solution of diethyl [1-(2-methoxy-4-nitrophenyl)-2-oxo-1,2-dihydropyridin-3-yl]malonate (maximum 0.12 mol) was diluted with 390 ml of water, and 39 ml of concentrated sodium hydroxide solution were slowly added. The reaction mixture was stirred at 45° C. for 90 min, cooled to RT, diluted with water and extracted three times with dichloromethane. The organic phase was discarded, and the aqueous phase was admixed with 300 ml of dichloromethane and adjusted to pH 1 at 15° C. with concentrated hydrochloric acid. Even in a weakly acidic medium, the evolution of carbon dioxide arises. After warming to RT, stirring was carried out for 1 h, then the phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated to dryness on a rotary evaporator. The residue was stirred with acetonitrile, filtered with suction, after-washed and dried in vacuo. This gave 17.4 g (49%) of the desired compound. The mother liquor was evaporated to dryness, stirred with acetonitrile and worked-up analogously. This gave a further 3.6 g (10%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:41]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:36]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1)(=[O:37])[NH2:41]
Reactant: CCN=C=NCCCN(C)C
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 50.1 %

Procedure:
A solution of (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (540 mg), 1H-1,2,3-benzotriazol-1-01 ammonium salt (345 mg) and WSC.HCl (383 mg) in DMF (10 ml) was stirred at room temperature for 24 hr, and the mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object product (270 mg).
Reaction SMILES: CC(C)C[N:4]1[CH2:8][C:7](=[O:9])[NH:6]C1C(C)C.[OH:14][CH:15]([CH3:20])[CH2:16][C:17]([O-:19])=O.C(O)(=O)C1C=CC=CC=1.O>C(O)CCCC>[OH:14][CH:15]1[CH2:20][N:4]([CH2:8][C:7]([NH2:6])=[O:9])[C:17](=[O:19])[CH2:16]1
Reactant: CC(C)CN1CC(=O)NC1C(C)C
Reactant: CC(O)CC(=O)[O-]
Agent: O=C(O)c1ccccc1
Solvent: CCCCCO
Solvent: O
Product: NC(=O)CN1CC(O)CC1=O
Yield: 62.1 %

Procedure:
A solution of 2-methylpropyl 2-(1-methylethyl)-4-oxoimidazolidine-β-hydroxybutanoate (15 g, 52.4 mmol), benzoic acid (6.4 g, 52.4 mmol) and water (3.75 ml, 208 mmol) in n-pentanol (90 ml) was refluxed under nitrogen for 6 hr. After cooling the mixture was extracted twice with water (35 ml). The aqueous extracts were evaporated to dryness and the residue was crystallized from methanol to give 5.15 g (62.1%) of the title compound, m.p. 167°-70° C.
Reaction SMILES: Cl.NC1C2C(=CC(CC(NC(=O)CNS(C3C(C)=C(C)C4OC(C)(C)CCC=4C=3C)(=O)=O)C(=O)N3CCCCC3)=CC=2)C=CN=1.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][C:53]([CH2:57][CH:58]([NH:67]C(=O)OC(C)(C)C)[C:59](=[O:66])[N:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1.[CH3:75][C:76]([O:79][C:80](=[O:98])[CH2:81][C@H:82]([NH:86][S:87]([C:90]1[CH:95]=[CH:94][C:93]([O:96][CH3:97])=[CH:92][CH:91]=1)(=[O:89])=[O:88])[C:83](O)=[O:84])([CH3:78])[CH3:77].N[C@H](C(O)=O)CC(=O)OC(C)(C)C.COC1C=CC(S([Cl:123])(=O)=O)=CC=1>>[ClH:123].[CH3:78][C:76]([O:79][C:80](=[O:98])[CH2:81][C@H:82]([NH:86][S:87]([C:90]1[CH:91]=[CH:92][C:93]([O:96][CH3:97])=[CH:94][CH:95]=1)(=[O:89])=[O:88])[C:83]([NH:67][CH:58]([CH2:57][C:53]1[CH:52]=[C:51]2[C:56](=[CH:55][CH:54]=1)[C:47]([NH2:46])=[N:48][CH:49]=[CH:50]2)[C:59](=[O:66])[N:60]1[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]1)=[O:84])([CH3:75])[CH3:77]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Reactant: COc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Product: COc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)cc1

Procedure:
The procedure described for 5c was used. Deprotection of 100 mg of 5a and coupling with 99 mg of (2S)-[[(4-methoxyphenyl)sulfonyl]amino]butanedioic acid 4-(1,1-dimethylethyl)ester (prepared from Asp(OtBu)-OH and 4-methoxyphenylsulfonylchloride using the procedure described for 5b) yielded the title compound (85 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.25-1.67 (6H, m), 1.32 and 1.35 (9H, 2× s), 2.18-2.48 (2H, m), 3.96-3.55 (6H, m), 3.83 and 3.86 (3H, 2× s), 4.04-4.14 (1H, m), 5.05-5.17 (1H, m), 6.99-7.05 (2H, m), 7.19-7.23 (1H, m), 7.51-7.79 (5H, m), 8.30-8.36 (1H, m).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[CH2:18]([S:22]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCS(=O)(=O)Cl
Reactant: On1nnc2ccccc21
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)On1nnc2ccccc21
Reaction time: 4 h
Yield: 96.7 %

Procedure:
In benzene (50 ml) are dissolved 1-hydroxy-1,2,3-benzotriazole (6.8 g) and triethylamine (7.0 ml) and thereto is added dropwise a solution of n-butanesulfonyl chloride (7.8 g) in benzene (10 ml) at room temperature and the mixture is stirred for 4 hours. After the reaction, the benzene layer is separated, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 1-(n-butanesulfonyloxy)-1,2,3-benzotriazole (12.3 g) as an oily substance. Infrared spectrum (film): 1395, 1175 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:34][C@H:35]2[O:37][CH2:36]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:34][C@@H:35]2[CH2:36][O:37]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: O=C1CCc2c(O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1CCc2c(OC[C@@H]3CO3)ccc(OCc3ccccc3)c2N1
Yield: 82.1 %

Procedure:
A mixture of 8-(benzyloxy)-5-hydroxy-3,4-dihydro-2(1H)-quinolinone (0.20 g, 0.743 mmol), (S)-(+)-glycidyl 3-nitrobenzenesulfonate (0.193 g, 0.743 mmol) and potassium carbonate (0.113 g, 0.817 mmol) in 2-butanone (10 mL) was heated at reflux for 16 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (chloroform-methanol, 50:1) to yield the title compound (0.210 g, 0.61 mmol).
Reaction SMILES: Cl.N[C@@H:3]([CH2:22]CC1C=CC=CC=1)[C:4]([NH:6][C@@H](CC(C)C)C(OCC1C=CC=CC=1)=O)=[O:5].CC(C)C[C@H](NC(=O)[C@@H](NC(=O)CN1CCOCC1)CCC1C=CC=CC=1)C([NH:36][C@@H](CC1C=CC=CC=1)C(N[C@@H](CC(C)C)C([C@@]1(C)CO1)=O)=O)=O.[C:82]([OH:88])([C:84](F)(F)F)=[O:83]>CO>[NH:6]([C:4](=[O:5])[CH2:3][CH2:22][CH2:84][C:82]([OH:88])=[O:83])[NH2:36]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@@]1(C)CO1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: NNC(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Referring to FIG. 44, 5-hydrazinyl-5-oxopentanoic acid (2, 0.600 g, 4.14 mmol), (S)-4-methyl-N—((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide (1.97 g, 2.74 mmol) and TFA (100 μl) in methanol (20 ml) were stirred at room temperature for 5 days. The mixture was evaporated and the residue purified by prep HPLC (C18 column, acetonitrile/water) to give product as an oil; (601 mg, 29%).
Reaction SMILES: BrC[CH2:3][CH2:4][CH:5]([CH3:11])[CH:6]([CH3:10])[C:7]([OH:9])=[O:8].C(O)(=O)C(C)C.[Cl:18]CCCCl>>[Cl:18][CH2:3][CH2:4][CH:5]([CH3:11])[CH:6]([CH3:10])[C:7]([OH:9])=[O:8]
Reactant: ClCCCCl
Reactant: CC(CCCBr)C(C)C(=O)O
Solvent: CC(C)C(=O)O
Product: CC(CCCl)C(C)C(=O)O

Procedure:
The title compound was prepared as described for 6-bromo-2,3-dimethylhexanoic acid from isobutyric acid (9.67 g, 109.8 mmol), and 1,3-dichloropropane (37.2 g, 329.2 mmol). The product was purified by flash chromatography (CHCl3) to provide the acid (0.9 g, 5%) as a oil, HRMS (M+Li)+ calcd for C7H13O2ClLi 171.0764, found 171.0766.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[CH3:7].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].N1CCCCC1>CCO.O>[CH3:7][C:6]1[NH:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=1
Reactant: N#CCC(N)=O
Reactant: COCC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: COCc1cc(C)[nH]c(=O)c1C#N
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
1-(Methyloxy)-2,4-pentanedione (9.51 g, 73.12 mmol) and cyanoacetamide (6.17 g, 73.12 mmol) were dissolved in EtOH (76 mL) and heated until homogenous (ca. 75° C.). Piperidine (6.25 g, 73.12 mmol) was added and the reaction mixture heated at reflux for 20 mins, followed by cooling to room temperature. The contents were filtered to give a solid which was suspended in 140 mL water and stirred vigorously for 20 min. The heterogenous mixture was filtered to afford 6-methyl-4-[(methyloxy)methyl]-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (7.8 g, 65.6%). LCMS MH+=179.0 1H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 6.26 (s, 1H), 4.40 (s, 2H), 3.29 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]1([C:11]23[CH2:22][CH:15]4[CH2:16][C:17]([C:19](=[O:21])C)([CH2:18]2)[CH:13]([CH2:14]4)[CH2:12]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[O:24]C(C)(C)C>O.O1CCOCC1>[C:5]1([C:11]23[CH2:22][CH:15]4[CH2:16][C:17]([C:19]([OH:24])=[O:21])([CH2:18]2)[CH:13]([CH2:14]4)[CH2:12]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(C)(C)C
Reactant: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C12CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 25 °C

Procedure:
Dioxane (1.81) was added to a solution, cooled to −22° C., of sodium hydroxide (724 g) in water (4.8 l). Bromine (578 g) was metered into this solution such that a temperature of −15° C. was not exceeded. A solution of 1-(2-phenylhexahydro-2,5-methanopentalen-3a-yl)ethanone (290 g) in dioxane (600 ml) was metered into this solution, and the reaction was allowed to warm up gradually to room temperature. tert-Butyl methyl ether was added. Subsequently, water was metered in (2.5 l). After phase separation, the aqueous phase was washed with tert-butyl methyl ether. Subsequently, after addition of tert-butyl methyl ether (5 l), hydrochloric acid (32%) was used to establish a pH of pH 1.5. After phase separation, the organic phase was washed repeatedly with water and clarified with activated carbon. The solvent was changed by distillation under reduced pressure with addition of diisopropyl ether. After extractive stirring with diisopropyl ether at reflux, 2-phenylhexahydro-2,5-methanopentalene-3a-carboxylic acid (292 g) was obtained as a solid with 95% purity.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][NH:9][CH2:10][C:4]=2[CH:3]=1.[C:14]([O:18][C:19](=[O:22])[CH2:20]Br)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.O>[C:14]([O:18][C:19](=[O:22])[CH2:20][N:9]1[CH2:10][C:4]2[CH:3]=[C:2]([Br:1])[CH:13]=[N:12][C:5]=2[NH:6][C:7](=[O:11])[CH2:8]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CNCc2cc(Br)cnc2N1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC(=O)Nc2ncc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A solution of 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (2.29 g, 9.46 mmol) in DMF (100 mL) was treated with tert-butylbromoacetate (1.7 mL, 12 mmol) and triethylamine (1.5 mL, 11 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (300 mL) and then extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 2:1) gave the title compound (1.61 g, 48%) as a white powder: MS (ESI) t/e 356 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)[CH2:10][CH2:9][CH:8]([CH2:11]O)[CH2:7][CH2:6]1)=[O:4].C(N(S(F)(F)[F:40])CC)C>C(Cl)Cl>[F:40][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)([C:3]([OH:2])=[O:4])[CH2:6][CH2:7]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCC(CO)CC1
Solvent: ClCCl
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC(CF)CC2)cc1OCCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The compound of step 1 of example 58 (100 mg, 0.220 mmol) was dissolved in DCM (2 ml), diethylaminosulfur trifluoride (35 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 72 h. The mixture was partitioned between EA and aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) and hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:10]1([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:16][Br:19])[CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cc(OCc2ccccc2)ccc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(OCc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of 4-chloro-3-(hydroxymethyl)phenol (for as preparation see Intermediate 12) (3.3 g, 20.8 mmol) in ethanol (30 ml) was added 2 M sodium hydroxide (10 ml, 20 mmol). To the mixture was added dropwise a solution of benzyl bromide (2.48 ml, 20.8 mmol, Aldrich) in ethanol (30 ml). The reaction was stirred under nitrogen overnight at ambient temperature. The ethanol was removed in vacuo to leave a cream solid and the residue partitioned between water (80 ml) and dichloromethane (60 ml). The phases were separated and the aqueous phase extracted with dichloromethane (40 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (40 ml) and the solvent removed in vacuo to leave a white solid (4.6 g). The sample was loaded in dichloromethane and purified on silica (2×100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give {2-chloro-5-[(phenylmethyl)oxy]phenyl}methanol as a clear oil (4.12 g). To a solution of {2-chloro-5-[(phenylmethyl)oxy]phenyl}methanol (1.22 g, 4.91 mmol) in DCM (25 ml) at −10 to −15° C., under nitrogen, was added a solution of phosphorus tribromide (0.463 ml, 4.91 mmol, Aldrich) in DCM (10 ml) dropwise. The solution was allowed to warm to ambient temperature and stirred for 3 h under nitrogen. To the reaction mixture in an ice-bath was added dropwise saturated aqueous sodium hydrogen carbonate (15 ml). The mixture was diluted with water (80 ml) and DCM (100 ml). The phases were separated and the aqueous phase washed with DCM (60 ml). The combined organic extracts were washed with water (50 ml). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to give 3-(bromomethyl)-4-chlorophenyl phenylmethyl ether as a colourless gum (1.11 g).
Reaction SMILES: C(=O)C(C)C.[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.N1C[CH:35]=[C:34]([C:37]2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)[CH2:33][CH2:32]1>>[CH3:35][CH:34]([CH2:33][CH3:32])[CH2:37][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)N1Cc2ccncc2C1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Agent: CC(C)C=O
Product: CCC(C)CN1CCC(Oc2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 429, substituting 2-methylbutanal for isobutyraldehyde and N-(4-(piperidin-4-yloxy)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, Pyridine-d5. Temp=90° C.) δ ppm 8.52-8.58 (m, 2H) 8.08 (s, 1H) 7.74 (d, J=8.85 Hz, 2H) 7.10 (d, J=4.58 Hz, 1H) 6.97-7.05 (m, 2H) 4.84 (d, J=6.71