Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:26](=[O:28])[CH3:27])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:27][C:26]([C:18]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)=[O:28])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc(OC)c1OC

Procedure:
The procedure described in Example 8 was repeated using 0.55 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.63 g of 3',4',5'-trimethoxyacetophenone Yield 0.50 g (44%), m p 213°-216° C.
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:25][O:26][CH2:27][CH3:28])[N:19]([CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:29][CH2:30][C:31](O)=[O:32])=[CH:10][C:9]=2[N:8]=1.ON1C2C=CC=CC=2N=N1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>O>[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:25][O:26][CH2:27][CH3:28])[N:19]([CH2:20][C:21]([CH3:23])([OH:24])[CH3:22])[C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:29][CH2:30][C:31]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:32])=[CH:10][C:9]=2[N:8]=1
Reactant: CCOCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C

Procedure:
A 20-ml glass vial was charged with anhydrous DMF (1 mL), 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (165 mg, 0.43 mmol), N-(3-dimethylaminopropyl)-N″-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol, 1.3 eq), 1-hydroxybenzotriazole (70.3 mg, 0.52 mmol, 1.3 eq), and morpholine (110 mg, 1.29 mmol, 3.0 eq). The reaction was maintained at ambient temperature overnight. The reaction mixture was poured into water (10 mL), and the resulting mixture was extracted with dichloromethane (3×10 mL). The chloroform fractions were combined and concentrated, and the residue was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide 1-[4-amino-2-(ethoxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 118-119° C.
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([OH:27])=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:38][CH3:39])(=O)=O.O>CN(C)C=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([O:27][CH2:38][CH3:39])=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1

Procedure:
In 10 ml of N,N-dimethylformamide were stirred 0.50 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, 0.20 g of anhydrous potassium carbonate and 0.22 ml of diethyl sulfate at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:7) to give 0.50 g of N-acetyl-N-(2-ethoxycarbonylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Br:15])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl-].[F:17][CH:18]([F:24])[C:19](OCC)=[O:20].[Cl-].[NH4+]>O1CCCC1.CO>[Br:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([CH:19]([OH:20])[CH:18]([F:24])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Reactant: CCOC(=O)C(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
To a solution of tert-butyl 3,5-dibromobenzoate (18.43 g, 54.9 mmol) in tetrahydrofuran (137 mL) at 0° C. was added isopropylmagnessium chloride (2.0 M in THF; 46.6 mL, 93 mmol). The reaction mixture was warmed to ambient temperature. The reaction was monitor by LC-MS for disappearance of tert-butyl 3,5-dibromobenzoate. The mixture was cooled back to 0° C. and ethyl difluoroacetate (13.7 mL, 137 mmol) was added. The mixture was stirred at 0° C. for 1 h, then warmed to ambient temperature. After 18 h, methanol and saturated ammonium chloride were added and the mixture was concentrated to remove organic solvents. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (4.04 g).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:36])[C:8]1=[O:37])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[CH2:29]([C:14]1[C:11]2[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:37])[N:9]([CH3:36])[C:10]=2[CH:17]=[N:16][C:15]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a solution of 3-(5-benzyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydro pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.097 mmol) in THF (0.5 mL) and water (0.5 mL) was added LiOH.H2O (8.18 mg, 0.194 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-benzyl-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (26.4 mg, 56% yield) as a white solid. 1H NMR (CDCl3) δ: 8.79 (s, 1H), 7.45-7.37 (m, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.24 (s, 2H), 7.22-7.11 (m, 3H), 6.86 (d, J=7.1 Hz, 2H), 4.71 (s, 2H), 4.18 (t, J=6.1 Hz, 2H), 3.73 (d, J=13.2 Hz, 3H), 3.42 (t, J=5.6 Hz, 2H), 1.88-1.76 (m, 2H). LCMS: MH+ 486 and TR=2.808 min
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[O:26][CH2:27][C:28]([F:31])([F:30])[F:29]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[O:26][CH2:27][C:28]([F:29])([F:31])[F:30]
Reactant: OB(O)c1ccc(F)c(OCC(F)(F)F)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(OCC(F)(F)F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H12F4N4O, 377. Found, 377.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[ClH:1].[NH:11]([C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ncnc2c1CCC2
Reactant: Nc1ccccc1
Solvent: CCO
Product: Cl
Product: c1ccc(Nc2ncnc3c2CCC3)cc1
Temperature: 100 °C
Yield: 59 %

Procedure:
To 3.1 g (0.02 mole) of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine were added 4.7 g (0.05 mole) of aniline and about 10 ml of ethanol; the mixture was then heated at 100° C. for about 10 minutes; the mixture quickly became a solution and then soon produced crystals. The mixture was then heated for a further 5 minutes, after which it was allowed to cool. The crystals produced were collected by filtration and then recrystallised from ethanol, to give 2.9 g (yield 59%) of the desiredCompound No. 2, in the form of yellow needles melting at 220° C. (with decomposition).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].[S:12]1[CH:16]=[C:15]([CH:17]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[C:14]2[CH:36]=[CH:37][CH:38]=[CH:39][C:13]1=2>CCOC(C)=O>[Cl-:1].[S:12]1[CH:16]=[C:15]([CH:17]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N+:23]([CH2:2][C:3](=[O:4])[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=4)([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[C:14]2[CH:36]=[CH:37][CH:38]=[CH:39][C:13]1=2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Reactant: O=C(CCl)Nc1ccccn1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1csc3ccccc13)C2)Nc1ccccn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
2-Chloro-N-(pyridin-2-yl)acetamide (43.5 mg, 0.25 mmol) was added portion-wise to a solution of (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (C19) (100 mg, 0.25 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by preparative HPLC (Eluent: CH3CN, H2O). The product was triturated with i-Pr2O, filtered and dried under vacuum at room temperature to obtain (R)-3-(2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-(pyridin-2-ylamino)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (31 mg, 21.6% yield).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([C:18]([O:20]CC)=[O:19])[CH2:12][CH2:11]2.Cl>CO>[ClH:1].[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2
Reactant: CCOC(=O)C1CCc2cc(Cc3ncc[nH]3)ccc2C1
Agent: Cl
Solvent: CO
Product: O=C(O)C1CCc2cc(Cc3ncc[nH]3)ccc2C1
Yield: 61.4 %

Procedure:
4.5 g of ethyl 6-(1-imidazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxlate hydrochloride was added to a mixture of 15 ml of concentrated hydrochloric acid and 30 ml of methanol and then the mixture was heated under reflux for 20 hours. The reaction mixture was concentrated in vacuo to give 2.52 g of 6-(1-imidazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid hydrochloride as colorless prisms with m.p. 193°-233° C.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.O1CCCC1.[Br:19][C:20]1[C:21](Cl)=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1>O>[Br:19][C:20]1[C:21]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(Br)c1
Reaction time: 0.67 h
Yield: 95.1 %

Procedure:
Triethylamine (191 mg) and morpholine (120 mg) were added to a tetrahydrofuran (4 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (300 mg), followed by stirring for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 3:1), and a yellow solid of 4-(3-bromo-5-nitropyridin-2-yl)morpholine (346 mg) was thus obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[N:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[C:7]([CH3:15])[N:6]=1)[CH2:2][CH3:3].C1COCC1.O.[OH-].[Li+]>CO.O>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]([CH3:15])[N:6]=1)[CH2:17][CH3:18]
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)c1nc(C)cc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To methyl 2-(dipropylamino)-6-methylpyrimidine-4-carboxylate (0.450 g, 1.79 mmol) in MeOH (2 mL), water (1 mL), and THF (1 mL) was added lithium hydroxide monohydrate (0.113 g, 2.68 mmol). The mixture was stirred at room temperature for 1 h and then MeOH and THF were removed under reduced pressure. The pH of the residue was adjusted to approximately 5 and the resulting mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated to give 2-(dipropylamino)-6-methylpyrimidine-4-carboxylic acid (0.351 g) as a yellow solid.
Reaction SMILES: CC(OC([N:8]1[C:12]2=[C:13]([Cl:28])[N:14]=[CH:15][C:16]([C:17](=[O:27])[N:18]([CH3:26])[CH2:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:11]2[C:10]([CH3:29])=[CH:9]1)=O)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34]>>[ClH:28].[CH3:26][N:18]([CH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:17]([C:16]1[C:11]2[C:10]([CH3:29])=[CH:9][NH:8][C:12]=2[C:13]([NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:31]([Cl:30])[CH:32]=2)=[N:14][CH:15]=1)=[O:27]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N(C)CC3CCOCC3)c12
Reactant: Nc1cccc(Cl)c1
Product: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)N(C)CC3CCOCC3)c12
Product: Cl

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-[methyl-(tetrahydro-pyran-4-ylmethyl)-carbamoyl]-pyrrolo[2,3-c]pyridine-1-carboxylic acid dimethyl-ethyl ester (120 mg) and 3-chloroaniline instead of 3-bromoaniline. Purified by Biotage chromatography over silica gel eluting with ethyl acetate rather than trituration with diethyl ether. The salt formation was as Example 4 (d) to afford the title compound (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[OH:11].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C1N2CCN(CC2)C1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13]
Reactant: COC(=O)c1ccc(Br)cc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a mixture of 4-bromo-2-hydroxy-benzoic acid methyl ester (Mori, N. et al, Bull Chem. Soc. Jpn. 1969, 42(2), 488-491) (29.3 g, 127 mmol) and dimethylthiocarbamoyl chloride (17.2 g, 140 mmol) in DMF at room temperature was added DABCO (21.3 g, 190 mmol). The resulting mixture, after being stirred at room temperature overnight, was diluted with water (1.25 L) and acidified to a pH of around 4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide 4-bromo-2-dimethylthiocarbamoyloxy-benzoic acid methyl ester as an off-white solid (36.8 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.84 (d, J=8.2 Hz, 1H), 7.43 (dd, J=8.6, 2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 3.83 (s, 3H), 3.45 (s, 3H), 3.38 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Cl)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)/C=C\C(O)=O>O1CCCC1.CC(C)=O>[CH2:8]([NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: ClCC=Cc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C(=Cc1ccccc1)CNCc1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
113 ml (818 mmol) of triethylamine were added to 96.4 g (600 mmol) of cinnamyl chloride in 800 ml of tetrahydrofuran, the mixture was heated to 60° C., and then 65.4 ml (600 mmol) of benzylamine were added dropwise. The mixture was refluxed for 3 h and then stirred at room temperature for 15 h. After concentration under water pump vacuum, the contents of the flask were partitioned between methyl t-butyl ether and water (pH=10). The organic phase was washed twice with water, dried with sodium sulfate and concentrated. The crude product (109 g) composed of mono- and bisadduct was dissolved in 400 ml of acetone, a solution of 48 g (413 mmol) of maleic acid in 250 ml of acetone was added while stirring and, after cooling, the precipitated solid was filtered off with suction. After washing with acetone, 60.0 g (30%) of N-cinnamylbenzylamine were isolated as maleate, melting point 169°-170° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=[O:18])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]([Cl:11])([OH:18])(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1
Product: O=S(=O)(O)Cl

Procedure:
38.1 g (0.2 mol) of 4-methylbenzenesulphonyl chloride are dissolved in 300 ml of carbon tetrachloride and treated with 35.6 g (0.2 mol) of N-bromosuccinimide and, after addition of 0.2 g (1.2 mmol) of azobisisobutyronitrile (ABU), the mixture is heated under reflux for 4 h. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography (petroleum ether/toluene 4:1, 50 μm particle size) and subsequent recrystallisation from 100 ml of cyclohexane gives 24.0 g (45% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:15]2[C:20]3[S:21][C:22]([CH:24]([CH3:26])[CH3:25])=[N:23][C:19]=3[CH2:18][CH2:17][N:16]=2)[CH:3]=1.[BH4-].[Na+].CCN(C(C)C)C(C)C.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>CCO.C(Cl)Cl>[CH2:42]([O:41][C:39]([N:16]1[CH2:17][CH2:18][C:19]2[N:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[S:21][C:20]=2[CH:15]1[C:4]1[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:40])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1=NCCc2nc(C(C)C)sc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(C(C)C)nc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of ethyl 2-(4-chloro-2-(2-isopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-4-yl)phenoxy)acetate (33 mg, 84 μmol, 1.0 eq.) in EtOH (5 mL), NaBH4 (3.5 mg, 92 μmol, 1.1 eq.) was added. The cooling bath was removed and the yellow solution was stirred at r.t. for 2 hours. The reaction mixture was poured in water (15 mL). The mixture was extracted with DCM (2×20 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. To an-ice cooled solution of the residue and DIPEA (43 μL, 252 μmol, 3.0 eq.) in DCM (5 mL), benzyl chloroformate (14 μL, 92 μmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 1 hour. The reaction was quenched with 1M aq. citric acid soln. (5 mL). The layers were separated. The aq. phase was extracted with DCM (3×5 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C[CH2:30][O:31]C(C)=O>>[CH2:16]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][C:30]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[O:7]3)[CH2:3][CH2:2]2)=[O:31])[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](CNC(=O)N2CCC3(CC2)OC(=O)c2ccccc23)CC1
Temperature: 60 °C

Procedure:
Add spiro[isobenzofuran-1,4′-piperidin]-3-one (100 mg, 0.49 mmol) to 1 mL of a ˜0.2 M stock solution of 1′-(trans-4-ethoxycarbonyl-cyclohexylmethyl) carbamoyl chloride (prepared from trans-4-aminomethyl-cyclohexanecarboxylic acid ethyl ester using the same procedure given in Example 15 step A) and heat to 60° C. for 16 hours. Cool the solution, dilute with EtOAc and wash with brine. Dry the solution (Na2SO4) and concentrate under reduced pressure. Purify the crude product using preparative plate chromatography and triturate the resulting material with ether to obtain 1′-(trans-4-ethoxycarbonyl-cyclohexylmethyl)carbamoyl-spiro[isobenzofuran-1,4′piperidin]-3-one as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:20]=C[C:18]([C@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:30].[Cu][C:32]#[N:33].[CH3:34]N1C(=O)CCC1.Cl>O>[C:32]([C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:34][C:18]([C@H:21]4[CH2:22][CH2:23][C@H:24]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:4][C:3]=1[F:30])#[N:33]
Reactant: CN1CCCC1=O
Reactant: N#C[Cu]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4cc(F)c(Br)c(F)c4)nc3)cc2)CC1
Agent: Cl
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4cc(F)c(C#N)c(F)c4)nc3)cc2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3.0 g (0.006 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine and 0.8 g (0.08 mol) of copper (I) cyanide were added to 30 cm3 of NMP and the solution was refluxed for 2 hours using a mantle heater. The solution was cooled to 60° C. and added to a solution of 3.2 g of FeC13.6H2O, 1.0 cm3 of concentrated hydrochloric acid and 4 cm3 of water. The resulting solution was allowed to sit on a warm water bath at 60° C. for one hour. The crystals formed were filtered out, washed with water and treated through a silica gel column using chloroform as the solvent. The chloroform was distilled off and the residue was recrystallized from a solvent mixture of acetone and chloroform to yield 1.3 g (0.003 mol) of 2-(4'-cyano-3',5'-difluorophenyl)-5-[4 '-(trans-4"-propylcyclohexyl)phenyl]pyrimidine. The phase transition temperature of this compound, as measured by DSC, was: ##STR36##