Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1COCCN1
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 105 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
In a 10 mL volume glass vessel equipped with a stirrer and a thermometer were placed 1.0 g (3.7 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 1.61 g (18.5 mmol) of morpholine, and 4 mL of methanol. The resulting mixture was stirred at 105° C. for 4 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 1.10 g (reaction yield: 93%) of 6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Li+].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccccn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 2-pyridylacetate (6.81 mL, 50 mmol) was added dropwise to LHMDS (1.0M in THF, 50 mL) and THF (65 mL) cooled to 0° C. After 30 minutes iodomethane (3.97 g, 63.5 mmol) was added to the solution. After stirring for 1 hour at 0° C. the solution was concentrated and the residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CHCl3-d): δ 8.56 (d, J=4.9 Hz, 1H); 7.66 (td, J=7.6, 1.8 Hz, 1H); 7.18 (dd, J=7.6, 4.9 Hz, 1H); 3.96 (q, J=7.2 Hz, 1H); 3.69 (s, 3H). 1.56 (d, J=7.2 Hz, 3H). m/z 166.5 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[NH:3]1.Cl.[NH:18]1[CH:22]=[N:21][C:20]([S:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[C:31]([CH2:33][NH2:34])[CH:30]=[CH:29][N:28]=2)=[N:19]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:34][CH2:33][C:31]2[CH:30]=[CH:29][N:28]=[C:27]([O:26][CH2:25][CH2:24][S:23][C:20]3[N:21]=[CH:22][NH:18][N:19]=3)[CH:32]=2)=[O:14])[NH:3]1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: NCc1ccnc(OCCSc2nc[nH]n2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(NCc1ccnc(OCCSc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 15 h
Yield: 35 %

Procedure:
A suspension of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (200 mg, 0.917 mmol), 1-(2-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}pyridin-4-yl)methanamine hydrochloride obtained in Reference Example is (343 mg, 1.19 mmol) and diisopropylethylamine (462 mg, 3.57 mmol) in DMA (5 mL) was stirred at 90° C. for 15 hr. After cooling the mixture to room temperature, the resulting solid was collected by filtration, and washed with ethanol. The obtained crude powder was recrystallized from ethanol to give the title compound as a white powder (135 mg, 35%).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(=O)(N(C)C)N(C)C.Br[CH:38]([CH3:40])[CH3:39]>O>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH:38]([CH3:40])[CH3:39])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: CC(C)Br
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)OC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C

Procedure:
A mixture of 10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt and 75 parts of hexamethylphosphoric triamide is stirred at 110° C for a while. It is cooled to 20° C and 3.7 parts of 2-bromopropane are added dropwise. After stirring for 4 hours, another 0.37 parts of 2-bromopropane is added dropwise. Upon completion, stirring is continued over week-end at room temperature. The reaction mixture is poured onto 150 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is dissolved in 1,1'-oxybisethane. The solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The oily residue is crystallized from hexane. The product is filtered off and recrystallized from hexane, yielding 1-methylethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 78.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][N:11](C=O)C.[C-]#N.[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.75 g (18.2 mmol) of the compound from Example 6A are initially introduced into 20 ml DMF, 979 mg (20.0 mmol) sodium cyanide are added and the mixture is stirred at RT for 2 d. The reaction mixture is introduced on to a mixture of 250 ml saturated ammonium chloride solution and 200 ml ethyl acetate and the aqueous phase is extracted with ethyl acetate (three times with 100 ml each time). The combined organic phases are dried over sodium sulfate, filtered and concentrated and the residue is dried in vacuo. The product obtained in this way is reacted without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C.CCOC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Clc1ncccn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2ncccn2)CC1

Procedure:
As shown in step 5-i of Scheme 5, a mixture of tert-butyl ((cis)-4-aminocyclohexyl)carbamate (compound 1009, 490 mg, 2.3 mmol), 2-chloropyrimidine (262 mg, 2.3 mmol) and TEA (463 mg, 6374, 4.6 mmol) in DMF (10 mL) was subjected to microwave irradiation for 20 minutes at 150° C. The reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 50% EtOAc/hexanes gradient) to provide tert-butyl ((cis)-4-(pyrimidin-2-ylamino)cyclohexyl)carbamate (compound 1010) as a white solid: 1H-NMR (300 MHz, CDCl3) δ 8.28 (d, J=4.8 Hz, 2H), 6.53 (t, J=4.8 Hz, 1H), 5.12 (s, 1H), 4.56 (s, 1H), 3.99 (dq, J=7.0, 3.5 Hz, 1H), 3.65 (s, 1H), 1.83 (tq, J=10.2, 3.6 Hz, 5H), 1.66 (s, 8H), 8.13-7.91 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[S:4][N:3]=1.[Al](C)(C)[CH3:18]>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.O1CCOCC1>[F:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[C:5]1[S:4][N:3]=[C:2]([CH3:18])[C:6]=1[C:7]#[N:8]
Reactant: C[Al](C)C
Reactant: Cc1ccc(-c2snc(Cl)c2C#N)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2snc(C)c2C#N)c(F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile (500 mg, 1.98 mmol, 1.00 equiv), 1,4-dioxane (20 mL), Al(CH3)3 (6 mL), Pd(PPh3)4 (343 mg, 0.30 mmol, 0.15 equiv). The resulting solution was stirred for 3 h at 110° C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 200 mg (44%) of 5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazole-4-carbonitrile as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])C.[CH3:21][NH:22][CH3:23]>C(O)CO>[CH3:21][N:22]([CH3:23])[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5]
Reactant: CNC
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Solvent: OCCO
Product: Cc1c(C(=O)N(C)C)ncc2[nH]c3ccc(N)cc3c12
Temperature: 100 °C

Procedure:
0.3 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is suspended in 5 ml of ethylene glycol and, after the addition of 3 ml of dimethylamine, the whole is heated for 22 hours at 100° C. After cooling, the mixture is poured into 30 ml of ice water, extracted with ethyl acetate, washed with water until neutral, dried using sodium sulphate, filtered and the solvent is distilled off in vacuo. The crude product precipitates as a fine brown powder. 0.2 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid N,N-dimethylamide of melting point 235°-245° C. (decomposition) is obtained.
Reaction SMILES: [OH:1][CH:2]1[O:26][C:10]2=[CH:11][C:12]([O:14][CH:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:16])=[CH:13][C:8]3=[C:9]2[CH:4]([CH2:5][C:6]([CH3:28])([CH3:27])[O:7]3)[CH2:3]1.[CH2:29](O)C.CON>N1C=CC=CC=1>[CH3:29][O:1][CH:2]1[O:26][C:10]2=[CH:11][C:12]([O:14][CH:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:16])=[CH:13][C:8]3=[C:9]2[CH:4]([CH2:5][C:6]([CH3:27])([CH3:28])[O:7]3)[CH2:3]1
Reactant: CC(CCCc1ccccc1)Oc1cc2c3c(c1)OC(C)(C)CC3CC(O)O2
Reactant: CCO
Agent: CON
Solvent: c1ccncc1
Product: COC1CC2CC(C)(C)Oc3cc(OC(C)CCCc4ccccc4)cc(c32)O1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
In a stirred flask, under nitrogen, was placed (0.045 mole) 2-hydroxy-5,5-dimethyl-8-(5-phenyl-2-pentyloxy)-3,3a,4,5-tetrahydro-2H-pyrano[4,3,2-de]benzopyran, 250 ml ethanol and 250 ml pyridine. The solution was cooled to 0° C. and 3.94 g (0.047 mole) methoxyamine was added. The resulting mixture was stirred at 0° C. for 2.5 hours, the solvent evaporated in vacuo, the residue taken up in 500 ml ethyl ether and washed twice with water. The aqueous phase was backwashed with ether and the combined ether layers washed with brine and dried over anydrous magnesium sulfate. The solvent was evaporated in vacuo to obtain 19 g of residual oil. The structure of the product was verified by 1H-NMR. Mass spectrum (m/e): 411 (M+), 380 (M-OCH3), 364 (M-NH2OCH3).
Reaction SMILES: [CH:1]1([C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O>CS(C)=O>[CH:1]1([C:7]([CH3:11])([CH3:10])[CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(CO)C1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)(C=O)C1CCCCC1

Procedure:
2-Cyclohexyl-2-methyl-1-propanol, oxalyl chloride and dimethylsulfoxide were processed as described in Example 18A to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:21]=[N:22][N:23]([CH3:41])[C:24]=4[NH:25][C:26]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)[CH3:30])=[O:27])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].C1COCC1.[OH-].[Na+]>C(O)C>[CH3:41][N:23]1[C:24]([NH:25][C:26]([O:28][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)[CH3:30])=[O:27])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[CH:13][CH:12]=3)=[CH:15][CH:16]=2)[N:21]=[N:22]1
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nnn(C)c4NC(=O)OC(C)c4cccc(C(F)(F)F)c4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)nnn1C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
1-(4′-{1-Methyl-5-[1-(3-trifluoromethyl-phenyl)-ethoxycarbonylamino]-1H-[1,2,3]triazol-4-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid methyl ester (410 mg, 0.726 mmol) was dissolved 4 mL of THF and 4 mL of ethanol. To this stirred solution was added 1N sodium hydroxide solution (8 mL). The mixture was stirred at room temperature overnight. TLC indicated complete consumption of the starting material. The mixture was concentrated and the residue was dissolved in 15 mL of water. Dilute hydrochloric acid (1N, 9 mL) was added. The white solid was filtered and dried in the air to give 1-(4′-{1-methyl-5-[1-(3-trifluoromethyl-phenyl)-ethoxycarbonylamino]-1H-[1,2,3]triazol-4-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (400 mg, 100% yield). LC/MS calcd for C29H25F3N4O4 (m/e) 550.0, obsd 551.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.29 (m, 2.6H), 1.44-1.52 (m, 2H), 1.60 (br d, 2.4H), 3.86 (s, 3H), 5.75-5.95 (br m, 1H), 7.43 (d, J=8.1 Hz, 2.5H), 7.61 (d, J=8.1 Hz, 2.5H), 7.69 (br m, 3.5H), 7.79 (d, J=7.6 Hz, 3.5H), 9.65 and 10.05 (br s, 1H), 12.35 (s, 1H).
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13]2)[CH2:9][CH2:8]1.Cl.CN(C)CCCN=C=NCC.[N:33]1([C:39]2[N:40]=[C:41]([CH2:46][C:47]([O-])=[O:48])[NH:42][C:43](=[O:45])[CH:44]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[Na+]>CN(C)C=O>[N:33]1([C:39]2[N:40]=[C:41]([CH2:46][C:47](=[O:48])[N:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:10]4([CH2:11][CH2:12][O:7][CH2:8][CH2:9]4)[CH2:13]3)[NH:42][C:43](=[O:45])[CH:44]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1ccc2c(c1)NCC21CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CC2(CCOCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
3.8 ml of pyridine, 378 mg of 1,2,2′,3′,5′,6′-hexahydrospiro[3H-indole-3,4′-[4H]pyran] and 575 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 679 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 11.3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 25 ml of water and 20 ml of ethyl acetate, and then left to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 640 mg of 6-(morpholin-4-yl)-2-[2-oxo-2-(2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)ethyl]pyrimidin-4(3H)-one are thus obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1)([F:4])[CH3:3].O.O.[OH-].[Li+]>O1CCOCC1>[F:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1)([F:4])[CH3:3]
Reactant: COC(=O)c1cnc(C(C)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(F)(F)c1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.7 %

Procedure:
Methyl 5-(1,1-difluoroethyl)pyrazine-2-carboxylate (0.65 g, approx. purity 85%) was dissolved in dioxan (2 mL) and water (2 mL) was added, followed by lithium hydroxide monohydrate (54 mg, portionwise). After stirring at RT for 90 mins, the mixture was concentrated to 2 mL and Et2O (20 mL) added. The mixture was then extracted with NaOH (1 N, aq., 20 mL), and the aqueous portions acidified with 6N HCl to pH 2. The aqueous portion was then extracted with EtOAc, dried over MgSO4 and evaporated to afford the title compound as a white solid (119 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.11 (t, J=18.8 Hz, 3 H), 9.01 (d, J=1.3 Hz, 1 H), 9.47 (d, J=1.3 Hz, 1 H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:22]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:1][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=3)=[N:4][CH:3]=2)=[O:34])=[CH:36][CH:37]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCc1ccc(-c2ncc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2ncc(OC(=O)c3ccc(CCCCCCC)cc3)cn2)cc1

Procedure:
A mixture of 0.65 g of 5-methoxy-2-(4-n-octyl-phenyl)-pyrimidine [can be obtained by condensation of methyl β-hydroxy-α-methoxyacrylate with 4-n-octylbenzamidine hydrochloride, reaction of the 4-hydroxy-5-methoxypyrimidine obtained with P2S5 and reduction of the 4-mercaptopyrimidine obtained with a Raney nickel according to J. H. Chesterfield et al., J. Chem. Soc. 4590 (1960)] and 1.0 g of KOH in 15 ml of ethylene glycol are boiled for 10 hours. 10 ml of water are added to the cooled solution, which is then acidified using glacial acetic acid and extracted five times with ether. After conventional work-up, 5-hydroxy-2-(4-n-octylphenyl)-pyrimidine is obtained. (The other homologues can be obtained analogously). 0.26 g of the 5-hydroxy-2-(4-n-octylphenyl)pyrimidine obtained, 0.25 g of 4-n-heptylbenzoyl chloride and 0.15 g of potassium carbonate in 2.5 ml of dimethylformamide are subsequently heated at 100° C. for 12 hours with stirring. The salt is removed by filtration under suction, and the filtrate is concentrated to a residue, which is taken up in ether and washed with water until neutral. Conventional work-up gives 2-(4-n-octylphenyl)-pyrimidin-5-yl 4-n-heptylbenzoate.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=CC(C)C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:14][CH2:13][CH:12]([CH3:17])[CH3:4])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)CCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.083 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.62 Hz, 6 H) 1.44 (q, J=7.11 Hz, 2 H) 1.70 (m, 1 H) 3.03 (t, J=6.99 Hz, 2 H) 6.61 (s, 1 H) 7.43 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.54 Hz, 1 H) 7.65 (d, J=8.09 Hz, 1 H) 7.77 (t, J=7.72 Hz, 1 H) 7.92 (d, J=7.72 Hz, 1 H) 8.35 (d, J=5.52 Hz, 1 H) 14.20 (s, 1 H) 14.81 (s, 1 H). MS (ESI−) m/z 431 (M−H)−.
Reaction SMILES: [C:1]1([C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([OH:15])[C:13]=3[CH:14]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[Na+].[I-]>CC#N>[C:1]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([O:15][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Oc1cccc2[nH]c(C3=CCCC3)cc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C1=C(c2cc3c(OCCN4CCOCC4)cccc3[nH]2)CCC1
Temperature: 50 °C
Yield: 52 %

Procedure:
To 100 mg (0.503 mmol) of the intermediate 2-cyclopent-1-enyl-1H-indol-4-ol in 2 mL CH3CN was added 819 mg (2.51 mmol, 5 eq) cesium carbonate, 94 mg (0.503 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and a catalytic amount of NaI. The reaction mixture was heated at 50° C. for 3 h, partitioned between EtOAc and H2O, washed with aqueous NaCl solution, dried (MgSO4), and concentrated under vacuum to yield 81 mg (52%) of 2-cyclopent-1-enyl-4-(2-morpholin-4-yl-ethoxy)-1H-indole.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([F:28])[C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9])=C>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([F:28])[C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Solvent: CO
Product: O=C(NOCCO)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Yield: 47.6 %

Procedure:
A solution of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (200 mg, 0.39 mmol) in methanol (1 mL) was loaded onto an SCX-2 column. The column was washed with methanol (10 mL) then the product was then eluted with ammonia in methanol (20 mL, 2M), the appropriate fractions were concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (10-90% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organics were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (88 mg, 39%). LCMS (Method A): RT=7.71 min, [M+H]+=475. 1H NMR (DMSO-d6): 8.20 (1 H, s), 7.60 (1 H, s), 7.57 (1 H, dd, J=10.73, 1.96 Hz), 7.26 (1 H, dd, J=8.43, 1.82 Hz), 6.82 (1 H, d, J=11.14 Hz), 6.30 (1 H, t, J=8.71 Hz), 3.65 (2 H, t, J=4.77 Hz), 3.45 (2 H, t, J=4.68 Hz).
Reaction SMILES: C([NH:9][C:10]1[NH:14][N:13]=[C:12]([S:15]([NH:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])(=[O:17])=[O:16])[N:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>>[NH2:9][C:10]1[NH:14][N:13]=[C:12]([S:15]([NH:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])(=[O:17])=[O:16])[N:11]=1
Reactant: O=C(Nc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1
Yield: 72.7 %

Procedure:
A mixture of 16.9 g (0.045 mole) of 5-benzoylamino-N-(2,6-difluorophenyl)-1,2,4-triazole-3-sulfonamide and 75 ml of 6N sodium hydroxide was heated to reflux for a total of 4 hours. The resulting solution was treated with decolorizing carbon, filtered, and acidified with hydrochloric acid. The solids that formed were collected by filtration and dried to obtain a total of 14.8 g of crude product. This material was taken up dilute aqueous sodium hydroxide, treated again with decolorizing carbon, filtered and acidified to pH 5.0. The resulting slurry was chilled and the solids collected by filtration and dried to obtain 9.0 g of the title compound as a white solid, m.p. 255°-257° (dec.). The carbon nmr spectrum was consistent with the assigned structure and the melting point with that in the art.