Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5](O)=O)=O.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#C.C(OC(=O)C)(=O)C>CCCCCC>[C:8]1([N:3]2[CH:4]=[CH:5][C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:1]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CN(CC(=O)O)c1ccccc1
Reactant: C#CC(=O)OCC
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(-c2ccccc2)c1

Procedure:
A mixture of 2.69 g (15 mmole) of N-formyl-N-phenyl-glycine prepared in Reference Example 3, 5.47 g (55.8 mmole) of ethyl propiolate, and 15 ml of acetic anhydride was stirred using a magnetic stirrer over an oil bath at 130° C. for 22 hours. The reaction mixture was concentrated under vacuum. 22 ml of toluene was added to the residue and the mixture was evaporated under reduced pressure. This procedure was repeated to obtain a brown oily substance. This oily substance was purified using silica gel column chromatography (No. 9385 silica gel, manufactured by Merck Co., eluted with ethyl acetate:hexane=1:5 v/v) to obtain 2.8949 (yield 89.6%) of a light-yellow oil of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]1([N:35]([CH3:47])[C:36]([C:38]2[CH:39]=[CH:40][C:41]([NH:45][CH3:46])=[C:42]([CH:44]=2)[NH2:43])=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH3:47][N:35]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[C:36]([C:38]1[CH:39]=[CH:40][C:41]2[N:45]([CH3:46])[C:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:43][C:42]=2[CH:44]=1)=[O:37]
Reactant: CNc1ccc(C(=O)N(C)c2cccc3ccccc23)cc1N
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc2c(c1)nc(Cc1ccc(C#N)cc1)n2C)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
483 mg (3.0 mmol) of 4-cyanophenylacetic acid and 486 mg (3.0 mmol) of carbonyldiimidazole are dissolved in 20 ml tetrahydrofuran and stirred for 1 hour at 50° C. Then 916 mg 5-(naphthalen-1-yl-methylaminocarbonyl)-2-methylamino-aniline are added thereto and stirring is continued for a further 3 hours at 50° C. The solvent is concentrated by evaporation, the residue is combined with 30 ml glacial acetic acid and refluxed for 1 hour. After evaporation of the solvent the filtrate is chromatographed on silica gel, eluting with methylene chloride/ethanol 99:1, 98:1 and 97:1. The desired fractions are concentrated by evaporation, the residue is triturated with acetone/ether, suction filtered and dried.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1/[N:11]=[C:12]1\C(Cl)=NSS\1.[CH3:19][C:20]([CH3:25])([CH2:23][NH2:24])[CH2:21][NH2:22]>C1COCC1>[Br:10][C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:18])[N:22]3[CH2:21][C:20]([CH3:25])([CH3:19])[CH2:23][NH:24][C:12]3=[N:11]2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Br)cc1/N=c1/ssnc1Cl
Reactant: CC(C)(CN)CN
Solvent: C1CCOC1
Product: CC1(C)CNc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of (E)-methyl-4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate (0.1 g, 0.27 mmol) and 2,2-dimethylpropane-1,3-diamine (28 mg, 0.27 mmol) in dry THF was stirred for 2 h at room temperature, then the solvent was evaporated to give the crude product, which was purified by column chromatography to give 80 mg of the title compound. MS (ESI): 308, 310 (MH+).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].[CH2:12]([N:14]([CH2:36][CH3:37])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[C:22]([C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:26][CH:25]=2)=O)=[CH:17][CH:16]=1)[CH3:13].O>C(O)(=O)C>[OH:5][C:4]1[N:3]=[N:2][C:21]([C:18]2[CH:19]=[CH:20][C:15]([N:14]([CH2:36][CH3:37])[CH2:12][CH3:13])=[CH:16][CH:17]=2)=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[CH:28][CH:29]=2)[N:6]=1
Reactant: CCN(CC)c1ccc(C(=O)C(=O)c2ccc(N(CC)CC)cc2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)c1ccc(-c2nnc(O)nc2-c2ccc(N(CC)CC)cc2)cc1

Procedure:
Semicarbazide hydrochloride (1.57 g, 14.2 mmol) and sodium acetate (1.41 g, 17.3 mmol) are added to a solution of 1,2-bis(4-diethylaminophenyl)-ethane-1,2-dione prepared according to example 2 (5 g, 14.2 mmol) in acetic acid (20 ml). The mixture is heated at reflux for 12 hours. After returning to ambient temperature, the reaction mixture is poured into water. The raw solid is collected by filtration and washed with water. The residue is recrystallized in acetic acid. After filtration and washing with water, 3 g (54%) of a yellow solid are obtained after drying. δH (200 MHz, CDCl3), 1.18 (t; 12H), 3.45 (q; 8H), 6.65 (d; J 7.8; 4H), 7.87 (d; J 7.8; 4H), 10.4 (s; 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.[Na]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][CH:36]1[CH2:37][CH2:38][O:33][CH2:34][CH2:35]1
Reactant: COC(=O)c1ccncc1N
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1ccncc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 3-amino-isonicotinic acid methyl ester (500 mg, 3.29 mmol), dry N,N-dimethylformamide (10 mL), trifluoroacetic acid (1 mL) and sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 eq) was added tetrahydro-pyran-4-one (0.5 mL, 4.94 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 24 hours then poured into saturated sodium hydrogenocarbonate (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and evaporated to dryness affording the crude title compound as yellow syrup that was used as such for the next step.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:61])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]([C:21]2[C:31]3[O:30][CH2:29][C@H:28]([NH:32][C:33](=[O:45])[C@@H:34]([N:36](C(OC(C)(C)C)=O)[CH3:37])[CH3:35])[C:27](=[O:46])[N:26]([CH2:47][C:48]4[C:57]5[C:52](=[CH:53][C:54]([Br:58])=[CH:55][CH:56]=5)[CH:51]=[CH:50][C:49]=4[O:59][CH3:60])[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:61])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19]([C:21]2[C:31]3[O:30][CH2:29][C@H:28]([NH:32][C:33](=[O:45])[C@@H:34]([NH:36][CH3:37])[CH3:35])[C:27](=[O:46])[N:26]([CH2:47][C:48]4[C:57]5[C:52](=[CH:53][C:54]([Br:58])=[CH:55][CH:56]=5)[CH:51]=[CH:50][C:49]=4[O:59][CH3:60])[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cccc3c2OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N3Cc2c(OC)ccc3cc(Br)ccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H]1COc2c(C(=O)NCc3ccc(C(=O)OC)cc3)cccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Yield: 95.4 %

Procedure:
TFA (340 mg, 222 μl, 2.99 mmol, Eq: 200.00) was added to a solution of 4-[({(S)-9-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-7-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionyl amino]-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carbonyl}-amino)-methyl]-benzoic acid methyl ester (12 mg, 14.9 μmol, Eq: 1.00) in DCM (300 μl) at 0° C. After 1 h the mixture was concentrated and the residue dissolved in DCM. The solution was washed with sat. NaHCO3 and the NaHCO3 solution back extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was dissolved in a minimum of DCM. Et2O was added followed by pentane which resulted in a precipitate. The supernatant was decanted, the residue was washed with pentane and dried in vacuo to afford the title compound (10 mg, 95%) as a white solid. 1H NMR (DMSO-d6) δ: 8.81 (br. s., 1H), 8.22 (d, J=8.2 Hz, 1H), 8.03-8.12 (m, 2H), 7.87 (d, J=8.5 Hz, 2H), 7.79 (d, J=9.1 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.53 (dd, J=9.2, 2.0 Hz, 1H), 7.32-7.40 (m, 3H), 7.25-7.31 (m, 1H), 7.16-7.25 (m, 1H), 5.87 (d, J=14.8 Hz, 1H), 5.24 (d, J=14.8 Hz, 1H), 4.66-4.82 (m, 1H), 4.13-4.52 (m, 4H), 3.78 (s, 3H), 2.94 (d, J=6.9 Hz, 1H), 2.20 (s, 3H), 1.08 (d, J=6.9 Hz, 3H)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:41][CH2:40][CH2:39][C@@H:38]([NH2:42])[CH2:37]1>C(C(C)=O)C(C)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:36]2[CH2:37][C@H:38]([NH2:42])[CH2:39][CH2:40][CH2:41]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Reactant: N[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 95 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (11.5 gm) were added to the reaction mixture at 30° C. The reaction mixture was heated to 95° C. and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30° C. and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at 30° C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at room temperature (pH is 10). The mixture was stirred for one hour 30° C. and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45° C. Ethyl acetate (100 mL) was added to the residue and stirred for 3 hours at 30° C. Filtered the compound and washed with ethyl acetate (40 mL) and dried the compound at below 60° C. under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: FIG. 2, Purity: 98.72%
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16]([NH:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18]>CS(C)=O>[CH2:16]([N:19]([CH2:20][CH:21]=[CH2:22])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:17]=[CH2:18]
Reactant: O=Cc1ccc(F)cc1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCN(CC=C)c1ccc(C=O)cc1
Temperature: 157.5 °C

Procedure:
Under an Ar atmosphere, 2.16 ml p-fluorobenzaldehyde and 3 ml DMSO were added sequentially to 3.5 g (30 mmol) of anhydrous K2CO3 , 3.70 ml (20 mmol) diallylamine. With constant stirring, the mixture was heated to about 155-160° C. After refluxing for 20 hours, the solution became intense red. The mixture was cooled to room temperature and 10 ml distilled water was added to dissolve any inorganic salts and the product was extracted with ether. The water layer was washed with ether several times and the combined organic layers were dried over MgSO4. The ether solution was then filtered and the ether, unreacted starting materials and solvent DMSO were removed by vacuum distillation at 100° C. A very viscous orange red product was left in the flask. Yield=2.05 g (51%). Mass spectrum: M+ /e=201. Calcd. M+ /e=201.27 Anal. calcd. for C13H15NO, C, 77.58; H, 7.51; N, 6.96. Found: C, 77.33; H, 7.33; N, 6.66. 1H NMR(CDCl3), δ 9.71 (1H,s), 7.70 (2H, d, J=9Hz), 6.70 (2H, d, J=9Hz), 5.82 (2H, m), 5.19 (4H, m), 4.00 (4H,t). 13C NMR (CDCl3) δ 189.4, 152.8, 131.8, 116.8, 110.9, 52.22 ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=1.[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH2:26]>>[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:10]1[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][N:11]=1
Reactant: CSc1ncc(Cc2cccs2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2cccs2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone (1.43 g) and 2-(5-methyl- 4-imidazolylmethylthio)ethylamine (1.03 g) was heated at 140° for 6 hours. The cooled residue was washed with water to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thienylmethyl)-4-pyrimidone, and this product was treated with dilute ethanolic HCl to give the title compound in 40% yield, m.p. 172°-176° (ethanol-acetonitrile). The dihydrochloride was passed down an ion-exchange column of IRA 400 eluting with 1 N hydrobromic acid, and the eluate was evaporated to dryness and recrystallised from ethanol acetonitrile to give the corresponding dihydrobromide m.p. 199°-203°.
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[N:5]1([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:2]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)[CH2:6][CH2:7]1)[CH:3]=[CH2:4]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN1CCCN(c2ccc(C(=O)OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
3-Bromoprop-1-ene (0.433 mL, 5.00 mmol) was added to a stirred solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (1.242 g, 5 mmol) and DIPEA (2.183 mL, 12.50 mmol) in dichloromethane (20 mL). The reaction mixture was stirred under nitrogen at room temperature for 24 h. This was diluted with dichloromethane (20 mL), washed with water (2×25 ml) and saturated sodium chloride solution (20 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-allyl-1,4-diazepan-1-yl)benzoate (0.700 g, 48.5%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[CH2:13](O)[CH3:14].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCO
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 25.2 g of indoline-2-carboxylic acid, 50 ml of ethanol and 200 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at room temperature for 3 days. At the end of this time, the reaction mixture was poured into an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 28.1 g of the title compound having Rf=0.81 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[C:3]1SC>CO.[Ni].O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[CH:3]1
Reactant: CNc1cc(=O)n(C)c(SC)n1
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CNc1cc(=O)n(C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Referring to scheme 1, 3-methyl-6-(methylamino)-2-(methylthio)pyrimidin-4(3H)-one (compound 1A; 650 mg, 0.35 mmol, 1 eq) was suspended in methanol (5 ml). A large excess of Raney Nickel slurried in water was added (approx 5 ml) and the mixture stirred at room temperature overnight to yield compound 1B. The product was confirmed by LC-MS. The mixture was filtered and the solid washed several times with methanol. The filtrate was then removed in vacuo and the residue was purified by flash chromatography with 1:10 MeOH:DCM to leave 3-methyl-6-(methylamino)pyrimidin-4(3H)-one (compound 1B) as a yellow/green solid (380 mg, 86%). 1H NMR (400 MHz, MeOD) δ ppm 2.78 (s, 3H) 3.35 (s, 3H) 5.22 (br. s., 1H) 8.10 (br. s., 1H); [M+H] calc'd for C5H7N3O, 126; found, 126.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13](C(OC(C)(C)C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2[nH]nc(NS(=O)(=O)c3ccc(Cl)s3)c12
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl 3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 6) (155 mg, 0.35 mmol) was dissolved in DCM (0.2 mL) and TFA (0.4 mL) was added. The solution was stood at room temperature for 30 min, and then blown down to dryness under a stream of nitrogen in a Radley's blow down unit to give the title compound (200 mg). LCMS (System D) RT=1.02 min, ES+ve m/z 344 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Mg].C(Br)CBr.[C:19]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]=[CH:6][CH:1]=[CH:2][C:3]=1[C:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[OH:26]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1)c1ccncc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccncc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 111.0 g (0.50 mole) of 4-biphenyl bromide in 200 ml of dry tetrahydrofuran (THF) was added slowly to a mixture of 12.10 g (0.5 gram-atom) of magnesium, 2 ml of ethylenedibromide and 200 ml of THF at such a rate as to maintain reflux. After addition the mixture was refluxed for 0.5 hours, cooled and treated over 0.5 hours with a solution of 82.3 g (0.45 mole) of 4-benzoylpyridine in 600 ml THF. The resulting slurry was stirred 0.5 hours at 25° C. and treated with 1000 ml 20% ammonium chloride solution. The organic layer was separated, filtered, the filtrate dried, filtered and stripped. The residue was triturated with ether and filtered. This solid was recrystallized from ethanol, chloroform, and finally toluene to give α-(1,4'-biphenyl)-yl-α-phenyl-4-pyridinemethanol as a white solid, m.p. after drying in vacuo at 70° C.; 173.5°-175.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[C:36](Cl)=[N:37][CH:38]=[C:39]([CH:45]=1)[C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:36]2[C:35]([Cl:34])=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][N:37]=2)[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 59.4 mg of ethyl 5,6-dichloronicotinate, and 37.3 mg of potassium carbonate was added 2.0 mL of DMSO at room temperature, and the mixed solution was stirred at 100° C. overnight. After cooling to room temperature, water was added thereto. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 128 mg of ethyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinate as a colorless foamy substance. FAB+: 628
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3C=NC=C[CH:16]=3)=[CH:10][C:5]2=[N:4][C:3]=1[NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19].N.C([OH:26])C>>[C:11]([C:9]1[CH:8]=[CH:7][N:6]2[CH:2]=[C:3]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[N:4]=[C:5]2[CH:10]=1)(=[O:26])[CH3:16]
Reactant: CCO
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)ccn2c1Cl
Agent: N
Product: CCNC(=O)Nc1cn2ccc(C(C)=O)cc2n1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a suspension of diester 2 (10.9 g, 31.9 mmol) in 50 mL ethanol was added 50 mL of 7M methanolic ammonia at 23° C. After 3 h, the copious precipitate was collected by vacuum filtration and dried under a stream of air to give 7.45 g (74%) of amide 3 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH:11]=O.[N:13]([CH2:16][C:17]([O:19][CH2:20]C)=[O:18])=[N+:14]=[N-:15].O>CO>[N:13](/[C:16](=[CH:11]\[CH:10]=[CH:9]\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])/[C:17]([O:19][CH3:20])=[O:18])=[N+:14]=[N-:15]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1ccccc1/C=C/C=O
Solvent: O
Solvent: CO
Product: COC(=O)/C(=C/C=C/c1ccccc1OC)N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
28%-Sodium metholate-methanol solution (4.4 ml) was diluted with methanol (5 ml), and cooled to −20° C. A solution of (2E)-3-(2-methoxyphenyl)prop-2-enal (2.4 g) and ethyl azidoacetate (7.5 g) in methanol (8 ml) was added over 30 min, and the mixture was stirred at −10° C. for 1 hr and at room temperature for 2 hr. The reaction mixture was poured into water and extracted with ether. The extract was washed with brine, and dried over anhydrous sodium 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 (1:4) was concentrated under reduced pressure to give methyl(2Z,4E)-2-azido-5-(2-methoxyphenyl)penta-2,4-dienoate (3.6 g). A part (3.5 g) thereof was dissolved in chloroform (10 ml), zinc iodide (214 mg) was added and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and extracted with 1,2-dichloroethane. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object product (3.26 g).