Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC12CCCNC2
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
An optically-active compound of 1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester (2.37 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.4 g), potassium carbonate (3.8 g) and water (71 ml), and heated to 100° C. to stir for 3 hours. The mixture was cooled to room temperature. Then, thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting residue was slurry-washed with n-hexane/ethyl acetate (1/1) solution to give the titled compound (2.55 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1)#[N:2].[C:19](OCC)(=O)C>S(=O)(=O)(O)O.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([O:16][CH3:19])=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(C)=O
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CC(C)CC(=O)Nc1ccc(C#N)cc1
Yield: 56 %

Procedure:
A solution of 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (940 mg, 3.82 mmol) and conc. sulfuric acid (1 drop) in methanol (25 mL) was heated with reflux for 14 hr. The reaction solution was cooled, and ethyl acetate was added thereto. The solution was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give methyl 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoate (557 mg, 2.139 mmol, 56.0%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl>[CH3:42][S:39]([O:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[N:18]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:14][CH2:13]1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask containing (trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methanol (obtained following example 2) (102 mg, 0.231 mmol) at 0° C. was added DCM (2 ml) and triethylamine (0.048 ml, 0.347 mmol), followed by dropwise addition of Mesyl Chloride (0.023 ml, 0.301 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 2 hr. The reaction mixture was diluted with DCM and washed with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to yield (trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methyl methanesulfonate (110 mg, 92% yield), LCMS (m/z): 519.2 (MH+), retention time=0.80 min. The resulting residue was used in next step without further purification.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].FC(F)(F)S(O)(=O)=O.[SH:59][C@@H:60]1[CH2:64][N:63]([CH3:65])[C@H:62]([C:66]([N:68]2[CH2:73][CH2:72][N:71]([C:74]([O:76][CH2:77][C:78]3[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=3)=[O:75])[CH2:70][CH2:69]2)=[O:67])[CH2:61]1>C(#N)C>[N+:84]([C:81]1[CH:82]=[CH:83][C:78]([CH2:77][O:76][C:74]([N:71]2[CH2:72][CH2:73][N:68]([C:66]([C@@H:62]3[CH2:61][C@H:60]([S:59][C:32]4[C@H:33]([CH3:34])[C@@H:29]5[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]5[C:31]=4[C:36]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)=[O:37])[CH2:64][N:63]3[CH3:65])=[O:67])[CH2:69][CH2:70]2)=[O:75])=[CH:79][CH:80]=1)([O-:86])=[O:85]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 39.2 %

Procedure:
7.0 g of diphenylphosphoryl chloride and 3.4 g of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 8.6 g of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 120 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 6.7 g of diisopropylethylamine and a solution of 13.8 g of (2S,4S)-4-mercapto-2-[4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-methylpyrrolidine trifluoromethanesulfonate in dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was allowed to stand overnight, whilst ice-cooling. At the end of this time, the reaction mixture was worked up and purified in a similar manner to that described in Example 49(a), to give 7.0 g of the title compound, as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH2:20])=[CH:6]2.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH:20][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[CH:6]2
Reactant: COc1ccc2c(c1)C=C(CN)C(c1ccccc1)O2
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC1=Cc2cc(OC)ccc2OC1c1ccccc1

Procedure:
A solution of 0.45 g (1.7 mmol) of the amine obtained in Step C of Example 42 in 15 ml of anhydrous dichloromethane is cooled to 0° C.; 0.7 ml (5.1 mmol) of triethylamine and also 0.26 ml (2.55 mmol) of butyryl chloride are then added to the medium. Stirring is maintained for 30 minutes; the reaction mixture is then adjusted to an acid pH with a 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the organic phase is then washed with a saturated solution of sodium hydrogen carbonate. The residue obtained after evaporation of the solvent in vacuo is passed over a silica column (eluant: AcOEt/PE: 60/40) to yield the title amide in the form of a white solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:30]=[C:31]([C:35]([NH:37][NH2:38])=O)[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:35]2[O:26][C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)=[N:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nnc(-c3cccc(Cl)c3)o2)C1

Procedure:
200 mg (0.518 mmol) of the compound from Example 49A and 97 mg (0.569 mmol) of 3-chlorobenzenecarbohydrazide were reacted according to the General Method 4. Yield: 13 mg (11% of theory).
Reaction SMILES: [Mg:1].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].CCOCC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26]>O.C1COCC1>[CH3:19][C:18]1[CH:22]=[CH:23][CH:24]=[CH:16][C:17]=1[Mg:1][Br:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2([OH:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: [Mg]
Reactant: Cc1ccccc1Br
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Product: Cc1ccccc1[Mg]Br
Reaction time: 4 h
Yield: 126.4 %

Procedure:
A solution of 2-methylphenylmagnesium bromide is prepared from 2.7 g of magnesium, 19 g of 1-bromo-2-methylbenzene and 100 ml of ether. A mixture of 5.04 g of 5-chloroisatin and 100 ml of THF is cooled in an ice bath under an argon atmosphere and the solution of magnesium compound prepared above is added slowly. After stirring for 4 hours, water is added and the solvents are evaporated off under vacuum. The residue is extracted with AcOEt, the precipitate formed is filtered off and the organic phase of the filtrate is dried over magnesium sulfate and evaporated under vacuum. The residue obtained, combined with the precipitate previously filtered off, is crystallized from MeOH to give 4.8 g of the expected product. M.p.=285°-295° C.
Reaction SMILES: C[Si]([C:5]#[C:6][Si](C)(C)C)(C)C.[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12].Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:18]([C:17]1[CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:23]([OH:24])=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1)(=[O:19])[C:5]#[CH:6]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: C#CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A solution of 3.40 g (20.0 mmol) of bis(trimethylsilyl)acetylene and 4.03 g (15.0 mmol) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride [which is prepared from 3,5-di-t-butyl-4-hydroxybenzoic acid by treatment with oxalyl chloride (benzene, 60°, 2h)] in 80 mL of methylene chloride is treated at -78° with 1.78 mL (16.5 mmol) of titanium tetrachloride. The resulting dark mixture is stirred at -78° for 30 minutes and then is allowed to warm to 0° and stirred for an additional 30 minutes. The reaction solution is poured into 3N HCl and the layers are separated. The aqueous portion is extracted with pentane and the combined organic phase is washed with sat. NaCl and dried (MgSO4). The crude silylacetylene intermediate is concentrated, dissolved in 100 mL of methanol and then is treated at room temperature with 20 mL of 0.01M borax. After stirring the mixture at 25° overnight, it is poured into 3N HCl and the aqueous layer is extracted with pentane. The combined organic phase is washed with sat. NaCl and dried (MgSO4). Recyrstallization from hexane affords 2.40 g (62%) of the title compound: mp 100°-101°; IR (CCl4) 3620(s), 3300(m), 2950(s), 2090(m), 1640(s), 1580(s), 1290(s), 1215(vs) cm-1 ; 1H-NMR (CDCl3)δ(ppm) 1.45(s, 18H), 3.30(s, 1H), 5.80(s, 1H), 8.00(s, 2H); 13C-NMR (CDCl3)δ30.09, 34.41, 79.84, 80.80, 127.76, 128.51, 136.34, 160.02, 176.67 ppm.
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[NH:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH:44]([OH:46])[CH3:45]>>[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][C:23]2[C:9]([N:39]3[CH2:43][CH2:42][CH2:41][CH:40]3[CH:44]([OH:46])[CH3:45])=[CH:10][C:11]3[NH:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:13][C:12]=3[CH:22]=2)=[CH:30][CH:29]=1)(=[O:33])=[O:32]
Reactant: CC(O)C1CCCN1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Product: CC(O)C1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid, diastereomer mixture, in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 1-pyrrolidin-2-yl-ethanol. The resulting diastereomer mixture was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) into the individual diastereomers A and B each as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:32])[C:17]([CH3:31])=[C:18]([C:28]([NH2:30])=[O:29])[C:19]=1[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:32][C:16]1[C:17]([CH3:31])=[C:18]([C:28]([NH2:30])=[O:29])[C:19]([C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cc(F)cc(F)c2)c1C(N)=O
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cc(F)cc(F)c2)c1C(N)=O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 6-(1-aminoethyl)-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide (61 mg, 0.19 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.38 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H18ClF2N6O (M+H)+: m/z=443.1. found: 443.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[O:17])[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].C>C(O)(=O)C.[Zn]>[CH3:2][C:1]1[NH:15][C:14]2[C:13](=[O:16])[C:12]3[C:7]([C:6](=[O:17])[C:5]=2[N:4]=1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: CC(=O)NC1=C(N)C(=O)c2ccccc2C1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc2c([nH]1)C(=O)c1ccccc1C2=O

Procedure:
Method 2 (Acid-Promoted Cyclization): A solution of 3a (2.0 g, 0.0009 mol) and Zn (1.0 g) in glacial acetic acid (50 ml) was refluxed for 24 h. A small amount of activated charcoal was added, and the solution was then filtered. The filtrate was poured into a 4-fold excess of H2O. The pH was adjusted to 8 by addition of a solution of NaHCO3, and the resulting solution was then filtered. The recovered precipitate was recrystallized from EtOH to give a dark brown powder (4a).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][N:12]([CH3:16])[SH:13](=[O:15])=[O:14]>C(O)C.[Ni]>[NH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1].[CH3:11][N:12]([CH3:16])[SH:13](=[O:15])=[O:14]
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Agent: CN(C)[SH](=O)=O
Solvent: CCO
Product: Cc1ccccc1N

Procedure:
The compound 4-methyl-3-nitro-benzene-N,N-dimethylsulfonamide is dissolved in ethanol. A catalyst like Raney nickel is added and the mixture hydrogenated in a shaker. The catalyst is removed by filtration. The solvent is removed in vacuo to give a product which may be purified if necessary by chromatography or crystallization from an appropriate solvent like chloroform or heptane-ethyl acetate.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:23]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(CNCC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 2,2-diphenyl ethyl amine (10.0 g, 0.051 mol) and triethyl amine (20.5 g, 0.203 mol) in 200 mL tetrahydrofuran was added a solution of benzyl chloride (7.1 g, 0.056 mol) in 100 mL tetrahydrofuran. The reaction mixture was heated to reflux for 48 hours, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 300 mL chloroform and washed with 3×100 mL water. The organic layer was then stirred with 100 mL 2N NaOH solution for 30 minutes. The layers were separated and the aqueous layer was extracted further with 2×100 mL chloroform. The chloroform layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting oil was further purified by chromatography, eluting with hexane/ethyl acetate. 5.8 g of a clear oil was isolated which was characterized by analytical and spectroscopic properties as the hydrochloride salt, mp 250-253° C.
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH2:14][C@@H:13]1[CH2:28][OH:29])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH2:14][C@@H:13]1[CH:28]=[O:29])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)CC[C@@H]1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)CC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add sulfur trioxide pyridine complex (7.6 g, 47.8 mmol) in dimethylsulfoxide (27.0 mL, 382.4 mmol) to (2R, 5R)-5-Benzyloxymethoxy-2-hydroxymethyl-piperidine-1-carboxylic acid 1-tert-butyl ester (8.4 g, 23.90 mmol) in triethylamine (20.0 mL, 143.4 mmol) at 10° C. and stir at room temperature for 30 minutes. Add water and extract with diethyl ether. Combine the organic layers, wash with 5% citric acid followed by saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate to provide the desired compound. (8.0 g crude)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=O>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=O
Solvent: CCO
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 32.1 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (86.5 mg, 0.4 mmol) and 3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (88.9 mg, 0.4 mmol) in ethanol (2 mL) was stirred at room temperature for 4 days. The reaction was concentrated and the residue was column chromatographed to give 54 mg (32%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:22][CH:23]([NH2:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:28][CH:23]([CH3:22])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(OC)c1
Reactant: CC(N)C(C)(C)C
Product: COc1cc(NC(NC(C)C(C)(C)C)=C(C#N)S(C)(=O)=O)cc(OC)c1

Procedure:
3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfany-2-propenenitrile (0.263 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) gave the title compound as a syrup, 262 mg (86%). 1H NMR (200 MHz, CDCl3): δ=0.85 (s, 9H), 1.01 (d, 3H), 3.12 (s, 3H), 3.26 (m, 1H), 3.78 (s, 6H), 6.25 (d, 2H), 6.35 (t, 1H); EI SP/MS: 381 (M+).
Reaction SMILES: [NH2:1][C:2](N)=[O:3].[CH2:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Ni]>[C:2](=[O:3])([O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: OCc1ccccc1
Reactant: NC(N)=O
Agent: [Ni]
Product: NC(=O)OCc1ccccc1
Temperature: 131 °C
Yield: 97 %

Procedure:
A mixture of 240 parts of urea, 778 parts of benzyl alcohol and 11 parts of a cation exchanger which is commercially available under the registered name Amberlyst 15 and, having been treated in accordance with Example (1 a), contains nickel, is heated to the reflux temperature (131° C.) in a stirred vessel. In the course of 6 hours, the reflux temperature rises to 149° C. The reaction mixture is then heated at 149°-150° C. for a further 2 hours. After filtering off the exchanger, excess benzyl alcohol is removed by distillation under reduced pressure. 586 parts of benzyl carbamate are obtained. This corresponds to a yield of 97% of theory, based on urea. Benzyl carbamate boils at 116°-118° C. under from 0.3 to 0.4 mm Hg. Melting point= 75°-76° C. On distillation, a residue of 1% by weight is left.
Reaction SMILES: CC(OC([NH:8][C@@H:9]([CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)C.N>C(Cl)Cl.O>[NH2:8][C@@H:9]([CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CC#Cc1ccc(NCc2ccccc2F)cc1)NC(=O)OC(C)(C)C
Agent: N
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H](N)CC#Cc1ccc(NCc2ccccc2F)cc1
Yield: 89.9 %

Procedure:
A solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(4-{[(2-fluorophenyl)methyl]amino}phenyl)-4-pentynoate (D65, 192 mg, 0.450 mmol) in DCM containing 5% TFA (10.5 ml) was stirred at room temperature for 4.5 h. Then 28% NH3 in water was added and the mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and evaporated to afford the title compound (132 mg). The crude product was used unpurified in the next step. UPLC: 0.56 min, MS: (ES/+) m/z: 327 [MH]+, C19H19FN2O2 requires 326.