Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 4-(4-fluoro-phenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at room temperature to yield 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=376.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(NCCOC)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
To 2.4 g. (0.006 mole) of 5-chloro-7,8-dihydro-8-(2-methoxyethyl)-7-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in 100 ml. of ethanol was added 0.45 g. (0.006 mole) of 2-methoxyethylamine and 0.65 g. (0.006 mole) of Na2CO3. This mixture was refluxed 3 hours, then filtered and the filtrate chilled. A solid formed and was filtered off and rinsed with petroleum ether--m.p. 160°-163° C. No further purification was necessary.
Reaction SMILES: [CH2:1]([N:7]([C:14]1[C:15](OCC)=[N:16][S:17](=[O:20])(=[O:19])[N:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:24]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH2:31])([CH3:27])([CH3:26])[CH3:25]>CCO>[C:24]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:31][C:15]1[C:14]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:18][S:17](=[O:19])(=[O:20])[N:16]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1OCC
Solvent: CCO
Product: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of 4-(N,N-di-n-hexylamino)-3-ethoxy-1,1-dioxo-1,2,5-thiadiazole (400 mg, 1.02 mmol) and L-tyrosine t-butyl ester (261 mg, 1.1 mmol) in EtOH (10 mL) was stirred at room temperature for 36 hrs. The solvent was removed under reduced pressure residue purified by flash column chromatography (silica, hexane:EtOAc 3:1 then 1:1) to give the title compound as a white waxy solid (400 mg, 73%).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>C(O)C.O>[O:9]=[C:8]([CH3:10])[CH:7]([C:6]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCCCN1C(=O)c2ccccc2C1=O)C(C)=O
Reaction time: 8 h

Procedure:
A solution of sodium ethoxide in ethanol, prepared by dissolving 23.69 g (1.03 moles) of sodium in 800 ml of absolute alcohol, was treated slowly with ethyl acetoacetate. To this solution was added, in one portion, 308 g (1.04 moles) of N-(5-bromopentyl)phthalimide and the resulting mixture was refluxed for two hours and stirred overnight at 25°. The ethanol was stripped, 1500 ml of water was added to the residue, and the resulting mixture was extracted with 3×400 ml of ether. The ether layers were combined, dried over anhydrous sodium sulfate, filtered and stripped to give 350 g of light brown oil. This material was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29](=[O:39])[N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[C:6]=1[CH3:7].[Si:40]([O:47][CH2:48][CH2:49][O:50][C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[CH:56][C:57]([S:61]([NH2:64])(=[O:63])=[O:62])=[CH:58]2)=[CH:53][CH:52]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>>[CH2:35]([N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[C:29]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[NH:64][S:61]([C:57]3[CH:56]=[CH:55][C:54]4[C:59](=[CH:60][C:51]([O:50][CH2:49][CH2:48][O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])=[CH:52][CH:53]=4)[CH:58]=3)(=[O:63])=[O:62])=[CH:10][C:9]=2[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[N:4]=1)=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc2ccc(S(N)(=O)=O)cc2c1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(OCCO[Si](C)(C)C(C)(C)C)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 46.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 1,4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (Intermediate 1F, 40 mg, 0.073 mmol) and 7-(2-(tert-butyldimethylsilyloxy)ethoxy)naphthalene-2-sulfonamide (Intermediate 50B, 33 mg, 0.087 mmol) were converted to the title compound (31 mg, 47%) after purification using flash column chromatography (gradient from 0% to 3% MeOH/CH2Cl2). 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 8.62 (s, 1H), 8.11-8.09 (m, 1H), 7.97-7.96 (m, 1H), 7.89-7.88 (m, 2H), 7.84 (d, J=8.9 Hz, 1H), 7.55-7.52 (m, 1H), 7.40-7.38 (m, 2H), 7.23-7.07 (m, 3.5H), 6.85 (d, J=7.4 Hz, 0.5H), 4.75 (br s, 1H), 4.63 (br s, 1H), 4.42 (s, 1H), 4.27-4.24 (m, 2H), 3.85-3.81 (m, 2H), 3.46 (br s, 2H), 3.18-3.15 (m, 2H), 3.02 (br s, 1.5H), 2.84 (br s, 1.5H), 2.29 (s, 2H), 2.24 (s, 1H), 1.50-1.45 (m, 1H), 1.41-1.36 (m, 1H), 1.32-1.20 (m, 6H), 1.12-0.99 (m, 1H), 0.93-0.86 (m, 12H), 0.74 (t, J=7.4 Hz, 2H), 0.68 (t, J=7.2 Hz, 1H), 0.10 (s, 6H); MS(ESI+) m/z 914.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20](O)([CH:21](C)[CH2:22][CH:23]2[O:36][CH3:37])C(O)C(=O)N2C(CCCC2)C(=O)[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].[C:57](=[O:60])([O-])[O-:58].[K+].[K+]>CO>[CH2:1]([CH:4]([C:5](=[O:56])[CH2:6][CH2:7][CH:8]([CH3:55])[CH:9]([OH:10])[C:43]([CH3:54])=[CH:44][CH:45]1[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]1)[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]([OH:35])[CH:23]([O:36][CH3:37])[CH2:22][CH:21]([CH3:20])[C:57]([OH:58])=[O:60])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCC(C=C(C)CC(C)CC(OC)C(O)C(CC(C)C(=O)O)OC)C(=O)CCC(C)C(O)C(C)=CC1CCC(O)C(OC)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 17-allyl-1,2-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9 ]octacos-18-ene-3,10,16-trione (the compound of Example 15, European Patent Application No 323042) (2.5 g) and potassium carbonate (1.14 g) in methanol (25 ml) was stirred at ambient temperature for 1.5 hours, and then filtered. To the filtrate were added water and diethyl ether, and the separated aqueous layer was acidified with 1N hydrochloric acid. The precipitate was extracted with diethyl ether and the extract was washed with brine, dried and then concentrated in vacuo to give the crude subtitle compound.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[H][H].[Pd]>[C:1]1([CH:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Yield: 99.7 %

Procedure:
To a solution of 4-(phenyl(4-(trifluoromethyl)phenyl)methylene)piperidine (0.5 g, 1.57 mmol) in MeOH (15 mL) was added Pd/C (0.1 g) and the mixture was stirred in hydrogen at 3 atmospheric pressure for 12 h. It was filtered through silica gel pad, washed with MeOH and concentrated to give crude 4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidine (0.5 g, 98% yield) as a grey solid which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 320 (M+1).
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[Cl:14][C:15]1[C:16]([OH:37])=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:18]([OH:24])=[C:19]([CH:22]=[O:23])[C:20]=1[CH3:21].[CH3:38][C:39](O)([CH3:41])[CH3:40].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[C:16]([OH:37])=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][C:39]([CH3:41])([CH3:40])[CH3:38])=[O:35])[C:18]([OH:24])=[C:19]([CH:22]=[O:23])[C:20]=1[CH3:21]
Reactant: Cc1c(Cl)c(O)c(CCCCCCCCCC(=O)O)c(O)c1C=O
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1c(Cl)c(O)c(CCCCCCCCCC(=O)OC(C)(C)C)c(O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
TFAA (0.20 ml, 1.4 mmol) was added to a suspension of Compound 215-11-COOH (144 mg, 0.403 mmol) in toluene (5 ml) at 0° C., and the mixture was allowed to warm to room temperature with stirring for 30 minutes. After checking for complete dissolution of the raw material, the mixture was again cooled to 0° C. tBuOH (0.40 ml, 4.2 mmol) was added to the cooled mixture, which was allowed to warm to room temperature with stirring for 15 hours. A saturated aqueous NaHCO3 solution was added to the reaction solution, which was extracted with EtOAc twice after stirring for 5 minutes. The combined organic layer was washed with a saturated aqueous NaCl solution, and was dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (Hexane:EtOAc=7:1 to 4:1) followed by PTLC (Hexane:EtOAc=7:1) to yield the target product (28 mg, 17%).
Reaction SMILES: CI.[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[NH:14][C:15](=[O:20])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[N:14]([CH3:23])[C:15](=[O:20])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(=O)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c2c(c(=O)n(C)c1=O)CN(Cc1ccccc1)CC2
Temperature: 60 °C
Yield: 38.6 %

Procedure:
9.6 ml of methyl iodide were added dropwise at 40° C. over a period of 10 minutes, with stirring, to 40.7 g of 6-benzyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione and 20.7 g of potassium carbonate in 230 ml of dimethylformamide. After heating for 8 hours at 60° C., the mixture was concentrated under reduced pressure, the residue was taken up with water, the pH was adjusted to 8 and the mixture was worked up by extraction with dichloromethane and water. After the combined dichloromethane phases had been concentrated under reduced pressure, the residue was purified by chromatography on silica gel with dichloromethane/ethanol (volume ratio 95:5) to give 16.5 g of 6-benzyl-1,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimi-dine-2,4-dione, from which 6-benzyl-1,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione hydrochloride was obtained as a precipitate in diethyl ether with a solution of hydrochloric acid in ether. The product was recrystallized from methanol/diethyl ether and residual methanol was removed by the addition of water to the precipitate, concentration under reduced pressure and drying of the residue under high vacuum.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:20][CH:21]([CH3:23])[CH3:22])=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]([CH:13]([F:15])[F:14])=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([S:34][CH2:2][C:3]2[C:4]([CH2:20][CH:21]([CH3:23])[CH3:22])=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]([CH:13]([F:15])[F:14])=[N:7][C:8]=2[C:9]([F:12])([F:11])[F:10])=[CH:32][CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CCl)c1CC(C)C
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CSc2ccc(C(C)(C)C)cc2)c1CC(C)C

Procedure:
Reaction of methyl 5-chloromethyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 3 of U.S. Pat. No. 5,169,432) with 4-t-butylbenzenethiol according to the procedure of example 29 of U.S. Pat. No. 5,169,432 yielded the product as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[N:3]=1.[NH2:27][NH2:28]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][C:4]2[N:3]=[C:2]([NH:27][NH2:28])[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(CCCc2nc(Cl)cc(N3CCOCC3)n2)cc1OC
Reactant: NN
Product: COc1ccc(CCCc2nc(NN)cc(N3CCOCC3)n2)cc1OC
Yield: 88.9 %

Procedure:
Further, 4-chloro-2-[3-(3,4-dimethoxyphenyl)propyl]-6-morpholinopyrimidine (0.34 g, 0.90 mmol) was reacted with hydrazine (0.29 g, 9 mmol) to obtain 2-[3-(3,4-dimethoxyphenyl)propyl]-4-hydrazino-6-morpholinopyrimidine as a white solid (0.30 g, 0.80 mmol, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH:20]2[CH3:25]
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(Br)cccc21
Product: CC1c2cccc(Br)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[N+:17]([C:3]1[CH:4]=[C:5]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:6]=[CH:7][C:2]=1[S:27][C:24]1[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=1)([O-:19])=[O:18]
Reactant: Nc1ccc(S)cc1
Reactant: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 0 °C
Yield: 92.3 %

Procedure:
A solution of the compound from Example 216A (1.86 g, 6.95 mmol), 4-aminothiophenol (0.88 g, 7.00 mmol), cesium carbonate (2.3 g, 7.00 mmol) in dimethylformamide (10 ml) was heated at 40° C. for 16 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, and dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving an orange oil as the title compound, (2.35 g, 92%).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][C:14]2=[O:17])=[CH:9][CH:8]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:17])[NH:1][C:15]=2[CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC(=O)CCC2
Yield: 71.1 %

Procedure:
4 g of sodium azide are added portionwise to 8.3 g of 7-methoxy-1-tetralone in 36 ml of acetic acid. Then 17 ml of concentrated sulphuric acid are added dropwise, without a rise in temperature over 40°; the solution is poured onto ice and neutralised with 2 N sodium hydroxide solution. The separating bulk of crystals is removed and recrystallised from ethyl acetate. One obtains 6.4 g of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (m.p. 137°-138°).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].CN(C=O)C.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:14][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A cold (ice-bath) suspension of sodium hydride (0.55 mole, hexane washed) in 100 mL of dry THF was stirred under a nitrogen atmosphere while a solution of 2-oxazolidinone in 500 mL of 10:1 THF:DMF was added dropwise. The resulting gray suspension was warmed to room temperature and stirred for 24 hour. Benzyl bromide (66 mL, 0.056 mole) was added to the resulting white suspension and stirred at ambient temperature 24 hour. The reaction was quenched by careful addition of 26 mL water and the resulting mixture was concentrated and poured into 500 mL of water. After extraction with methylene chloride, the combined extracts were washed with water and brine and dried over magnesium sulfate. Concentration in vacuo afforded 104 g of a yellow oil which was purified by Kugelrohr distillation (bp 100°/0.1 mm) to give 81 g (92% yield) of the product as a colorless liquid which solidified on standing at room temperature to a colorless solid, m.p. 76°-78°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][O:2][C:3](=[O:9])[CH2:4][S:5]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:7])=[O:6]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To chlorosulfonyl-acetic acid methyl ester (3.39 g, 19.6 mmol) in dichloromethane (50 mL) is added morpholine (8.6 mL, 98 mmol). The resulting mixture is stirred at rt during 2 h and the solvent is evaporated to yield the title compound.
Reaction SMILES: C(Cl)(=O)C.[Br:5][C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]1[CH:13]=[C:14]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]([CH3:25])([N+:22]([O-])=O)[CH3:21]>CO.[Zn]>[NH2:22][C:20]([CH3:25])([CH3:21])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:29])[F:30])=[CH:13][C:12]=1[C:7]1[N:8]([CH3:11])[N:9]=[CH:10][C:6]=1[Br:5]
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)C(F)(F)F)ccc1OCC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)Cl
Solvent: CO
Product: Cn1ncc(Br)c1-c1cc(NC(=O)C(F)(F)F)ccc1OCC(C)(C)N
Temperature: 55 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
Acetylchloride (1.36 mL, 19.1 mmol) was added slowly to a well-stirred solution of N-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)-2,2,2-trifluoroacetamide (889 mg, 1.91 mmol) in methanol (10 mL). Zinc dust (1.25 g, 19.1 mmol) was added in small portions, and the mixture was stirred at 55° C. After 2 h, the solvent was removed under reduced pressure, and residue was suspended in 1M HCl (10 mL) and covered with ethyl acetate. The mixture was cooled on an ice bath, and ammonium hydroxide was added until all precipitate dissolved. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with sodium sulfate, filtered and evaporated to dryness to yield N-(4-(2-amino-2-methylpropoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl)-2,2,2-trifluoroacetamide as a white powder (693 mg, 1.59 mmol, 83%). LCMS m/z (%)=437.3 (M+H 81Br 9.0%), 435.2 (M+H 79Br 14.0%).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([CH3:33])[C:24]=1OS(C(F)(F)F)(=O)=O)[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][C:5]1[CH:6]=[C:7]([C:24]2[C:23]([CH3:33])=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[CH3:14])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(C)c(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: COCOc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(C)c(-c2cccc(O)c2)c(C)c1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 4.48 g (24 mmol) of 3-methoxymethoxyphenylboronic acid (described in Example 1(g)) with 7 g (22.4 mmol) of methyl 3,5-dimethyl-4-trifluoromethanesulphonyloxybenzoate, 24 mL of 2M potassium carbonate and 1.29 g (1.1 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.[CH:11]1(N)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:1][C:2]2[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)C1OC(N)=NC1=O
Reactant: NC1CCCCCC1
Product: CC(C)C1OC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and cycloheptylamine according to Method G+H.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:19]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1C
Reactant: NCCCCCCc1cccnc1
Product: Cc1ccc(-c2ccc(C(=O)NCCCCCCc3cccnc3)cc2)cc1C

Procedure:
The title compound was prepared from 7.0 g of 3',4'-dimethyl[1,1'-biphenyl]-4-carboxylic acid and 6.1 g of 3-pyridinehexanamine according to Example 3 to give 6.2 g of 3,'4'-dimethyl-N-[6-(3-pyridinyl)hexyl][1,1'-biphenyl]-4-carboxamide. mp 81°-82° C.