Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[CH:3]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18]C)=[O:17])=[C:8]1[CH3:20])([CH2:5][CH3:6])[CH3:4].[OH-].[Li+]>O>[CH:3]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[C:8]1[CH3:20])([CH2:5][CH3:6])[CH3:4]
Reactant: CCC(C)n1c(C)c(C(=O)OC)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)n1c(C)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a mixed solution of methanol (10 mL) and water (2 mL), methyl 1-sec-butyl-2-methyl-1H-indole-3-carboxylate (141 mg, 0.58 mmol) and lithium hydroxide (100 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrochloric (1 M) to adjust pH=6 and extracted with dichloromethane (10 mL×3). The organic layers were combined and concentrated to give 1-sec-butyl-2-methyl-1H-indole-3-carboxylic acid (97 mg, 72%).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[N:7]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[N:7]=1)(=[O:25])[CH3:24]
Reactant: Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In 30 ml of pyridine was dissolved 2.0 g hydrochloride of 2-amino-4-[4-(4-chlorobenzyloxy)phenyl]thiazole, and 1.0 ml of acetic anhydride was added to the solution, followed by stirring at room temperature for 2 hours. Water was added and, the precipitating crystals were recovered by filtration, thus yielding 1.9 g (95.0%) of 2-acetylamino-4-[4-(4-chlorobenzyloxy)phenyl]thiazole. m.p., 239°-240° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:4]=1)#[N:2].Cl.[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:4]=1
Reactant: CN(C)Cc1cc(C#N)ccn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)Cc1cc(CN)ccn1
Yield: 59.9 %

Procedure:
A mixture of 4-cyano-2-(dimethylamino)methylpyridine (800 mg, 4.97 mmol), palladium (80 mg, 10% Pd/C) and concentrated hydrochloric acid (3 mL) in methanol (30 mL) was shaken under 60 psi of hydrogen overnight. The reaction mixture was filtered through diatomaceous earth and the filter cake rinsed with water and methanol. The filtrate was concentrated under reduced pressure and the residue partitioned between water and methylene chloride. The aqueous layer was made alkaline with 1 N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give an orange oil. Purification by flash column chromatography (97:3 2-propanol/ammonium hydroxide) gave 4-aminomethyl-2-(dimethylamino) methylpyridine 37 (492 mg): 1H NMR (500 Hz, CDCl3) δ 8.50 (d, J=5.1 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=5.1 Hz, 1H), 3.91 (s, 2H), 3.58 (s, 2H), 2.30 (s, 6H); ESI MS m/z 166 [M+H]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]([OH:57])[C:34]2[C:35]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)=[C:36]3[C:41](=[CH:42][C:43]=2[CH:44]([CH3:46])[CH3:45])[O:40][C:39]([CH3:48])([CH3:47])[CH2:38][C:37]3=[O:49])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C(C1C=CC(C(O)C2C(C3C=CC(F)=CC=3)=C3C(=CC=2CCC)OC(C)(C)CC3=O)=CC=1)(C)(C)C>ClCCl>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([C:34]2[C:35]([C:50]3[CH:51]=[CH:52][C:53]([F:56])=[CH:54][CH:55]=3)=[C:36]3[C:41](=[CH:42][C:43]=2[CH:44]([CH3:46])[CH3:45])[O:40][C:39]([CH3:47])([CH3:48])[CH2:38][C:37]3=[O:49])=[O:57])=[CH:31][CH:32]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCCc1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Reaction time: 4 h

Procedure:
At 0° C., 340 mg (800 μmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one are added to a solution of 190 mg (400 μmol) of a 2:1 mixture of rac-6-[(4-tert-butylphenyl)(hydroxy)-methyl]-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 27A) and rac-6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-n-propyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one in 7.5 ml of dichloromethane, and the mixture is stirred at this temperature for 4 h. The mixture is then diluted with dichloromethane and washed three times with 1 M aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure, and the residue is purified by preparative HPLC (method 1) and subsequent column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/dichloromethane/ethyl acetate 20:20:0.5).
Reaction SMILES: C[C@H](N)C1C=CC=CC=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[C:16]([C@H:18]1[CH2:26][CH:25]=[CH:24][CH2:23][C@H:19]1[C:20]([OH:22])=O)=O)[CH3:11].[ClH:33].Cl.[NH:35]1[CH2:40][CH2:39][CH:38]([NH:41][NH2:42])[CH2:37][CH2:36]1>CC(O)C>[ClH:33].[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([C:16]2[C@@H:18]3[C@@H:19]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:20](=[O:22])[N:41]([CH:38]3[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]3)[N:42]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH3:11]
Reactant: CCOc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OCC
Reactant: NNC1CCNCC1
Agent: C[C@H](N)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CCOc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from the salt of (S)-(−)-α-methylbenzylamine, (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (compound P) and piperidin-4-yl-hydrazine dihydrochloride in 2-propanol as described for compound 5d. M. p. 248-250° C.
Reaction SMILES: [CH:1]12[CH2:16][O:15][CH2:14][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH:2]2[O:3]1.[I-].[Li+]>>[CH2:14]1[CH:13]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2](=[O:3])[CH:1]2[CH2:16][O:15]1
Reactant: C1CCCCC2OC2C2COCC2CCC1
Agent: [I-]
Agent: [Li+]
Product: O=C1CCCCCCCCCC2COCC12
Temperature: 200 °C
Yield: 53 %

Procedure:
3,15-Dioxa-tricyclo[11.3.0.0*2,4*]hexadecane from Step 1 (260 g, 1.16 mol) was mixed with lithium iodide (2.5 g, 18.7 mmol) and heated to 200° C. for 8 hours. The reaction was then cooled down and washed with water (500 mL). The crude was distilled to provide dodecahydro-2-oxa-cyclopentacyclododecen-4-one (138 g, ˜53% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[NH:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Product: CN(C)CCCNC(=O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12

Procedure:
2-(7-Trifluoromethyl-4-quinolylamino)benzoic acid is converted to the acid chloride which is reached with 3-dimethylaminopropylamine as in Example 1 to give the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[N:10]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>C1(C)C=CC=CC=1.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>[C:29]([C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[N:10]=1)(=[O:31])[CH3:30]
Reactant: O=C(CN1CCc2nc(Br)sc2C1)N1CCN(C2CCC2)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1nc2c(s1)CN(CC(=O)N1CCN(C3CCC3)CC1)CC2
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-5-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine (300 mg, 0.75 mmol), tributyl(1-ethoxy-vinyl)tin (361 mg, 1 mmol) and Pd(PPh3)4 (92 mg, 0.08 mmol) in toluene (15 mL) is degassed with argon and heated at 110° C. in a sealed tube overnight. The mixture is cooled and saturated KF solution (10 mL) is added. The mixture is stirred at rt for 30 min, and then the layers are separated. The aqueous layer is extracted with EtOAc (15 ml) and the combined extracts are dried and evaporated. The residue is dissolved in THF (10 mL), 2N HCl (10 mL) is added and the mixture is stirred at rt for 30 min. Solid Na2CO3 is added until pH>7 and the layers are separated. The aqueous layer is extracted with EtOAc (15 ml) and the combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a white solid. MS (M+1): 363.0; 1H NMR (δ, CDCl3): 3.88 (s, 2H), 3.52-3.62 (m, 4H), 3.41 (s, 2H), 2.99 (s, 4H), 2.62-2.77 (m, 4H), 2.29 (q, 4H), 1.66-2.08 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[S:5][CH:6]=1.[Cl:14][C:15]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([Cl:35])[Cl:34])[CH:27]=[C:26]([Cl:36])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:15]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([Cl:35])[Cl:34])[CH:27]=[C:26]([Cl:36])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: Cc1csc(-c2ccc(O)cc2)n1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)n1

Procedure:
96 mg of 4-(4-methyl-thiazol-2-yl)-phenol, 212 mg of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester and 207 mg of potassium carbonate are stirred for 24 hours at 50° C. in 3 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.23).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[NH2:25][NH2:26]>O1CCOCC1.O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH:25][NH:26][C:14]([C:13]3[C:9]([C:7]4[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[N:10][N:11]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)=[O:15])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: NN
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(NNC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 72 %

Procedure:
Add a solution of 476 mg of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride in 25 ml of dioxane dropwise to 210 mg of hydrazine dihydrochloride in 2 ml of water, whereupon N,N'-bis-[3-(5-nitro-2-furyl)-1-phenyl-4-pyrazolylcarbonyl]hydrazine [m.p. 313° to 314° C (with decomposition) from dimethylformamide] precipitates with a yield of 72%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:13][O:12][C:9]2=[C:10]([Br:22])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2onc(-c3ccccc3)c2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A mixture of 4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (388.1 mg, 1.37 mmol), N-bromosuccinimide (255 mg, 1.43 mmol), benzoyl peroxide (16 mg, 0.07 mmol), and carbon tetrachloride (10 ml) was refluxed for 3 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before it was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (432 mg): MS: (−) m/z 361.21, 363.23 (M−1, 79Br/81Br).
Reaction SMILES: [CH2:1]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[C:35](=[O:37])=[O:36].Cl>O1CCCC1>[CH2:22]([C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:21]2[CH:20]=[C:19]([C:35]([OH:37])=[O:36])[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C=O
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Into a flask fitted with a nitrogen inlet and rubber septum were introduced 2-bromo,-9,9-dioctylfluorene (34.18 g, 72.8 mmole) and dry tetrahydrofuran (300 mL). The solution was cooled to −60° C. and n-butyl lithium (29.1 mL, 2.5M in hexanes, 72.8 mmole) added via a syringe. The reaction mixture was observed to turn red. After stirring for 1 hour at −60° C., the reaction mixture was poured onto powdered dry-ice and left to stand overnight. The mixture was acidified with 1M HCl and extracted with chloroform. The chloroform extract was washed with water, dried over magnesium sulfate and concentrated to give the required acid as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[CH3:9][C:10]1([CH3:19])[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11]1>O>[CH3:9][C:10]1([CH3:19])[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:13]=2[O:14]1
Reactant: CC1(C)Oc2ccccc2O1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2O1
Reaction time: 0.25 h

Procedure:
A solution of 70% (conc.) nitric acid (20 ml) and glacial acetic acid (10 ml) cooled at 12° C. was treated by drops with 5 g (33.3 mmole) of the compound of Example 3A at a rate to maintain the temperature at 15°-20° C. Stirring was continued for 15 minutes after addition, then the brown slurry was diluted to 100 ml with water and filtered. The solid was washed with water, taken up in CH2Cl2, dried (Na2SO4) and evaporated to 5.40 g (83%) of pure yellow mononitro title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][C@H:10]2[CH2:11][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-tert-butyl-3-hydroxycyclobutylcarbamate (440 mg), p-toluenesulfonyl chloride (498 mg) and pyridine (0.74 mL) are dissolved in dichloromethane (7 mL) and a catalytic amount of 4-(dimethylamino)pyridine is added. The reaction mixture is stirred at ambient temperature overnight, concentrated, partitioned between ethyl acetate and water. The organic phase is washed with a 20% aqueous solution of citric acid, dried (MgSO4) and concentrated to give the title compound. Yield: 806 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)OCCC#N)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25]([NH2:28])(=O)[CH3:26].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][C:22]([CH2:26][CH2:25][NH2:28])=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(N)=O
Reactant: N#CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: NCCc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 110 °C
Yield: 63 %

Procedure:
1-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxy]-2-cyanoethane, m.p. 90°-93° C. which can be prepared by heating to 110° C. for 5 hours s mixture of 3-[2-[4-chlorophenylsulphonylamino)-ethyl]-phenoxy]-acetamide (1 mol), P2O5 (2 mol) and toluene. Yield 63% of theory; m.p. 94° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2Br)[N:8]=1)=[O:6].[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=C(OC)C=CC=2C2C=CC=CC=2)N=1)=O)(C)(C)C>>[OH:1][CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)[N:8]=1)=[O:6]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2Br)nc(O)c1OCc1ccccc1
Agent: COc1ccc(-c2ccccc2)c(Cc2nc(O)c(OCc3ccccc3)c(C(=O)OC(C)(C)C)n2)c1
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2-c2ccncc2)nc(O)c1OCc1ccccc1
Yield: 56.6 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(2-pyridin-4-yl-benzyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (152) (251 mg, 56.02%) as an off-white solid was synthesized from 5-benzyloxy-2-(2-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (151) (450 mg, 0.89 mmol) and pyridine-4-boronic acid (165.78 mg, 1.34 mmol) following the procedure as described for 5-benzyloxy-6-hydroxy-2-(4-methoxybiphenyl-2-ylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (139).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Cl:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1Cl)C(C)CNCC2
Reaction time: 8 h
Yield: 114.4 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (23 mg, 0.066 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 19 mg of a white solid. 1H NMR (400 MHz, CD3OD) d 7.12 (s, 1 H), 6.81 (s, 1 H), 6.03 (m, 1 H), 5.43 (d, J=17 Hz, 1 H), 5.24 (d, J=10 Hz, 1 H), 4.57 (d, J=5 Hz, 2 H), 3.1-2.9 (m, 5 H), 2.81 (m, 1 H), 2.63 (m, 1 H), 1.30 (d, J=7 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[C:7]([CH2:10][CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)=[CH:8][O:9][C:5]=2[CH:4]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)([OH:34])[CH2:30][CH2:29]1>>[OH:34][C:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:32][CH2:33][CH:28]([NH:27][C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([O:12][CH2:11][CH2:10][C:7]2[C:6]4[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:9][CH:8]=2)[CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:29][CH2:30]1
Reactant: COc1ccc2c(CCOc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1ccc2c(CCOc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(6-methoxy-benzofuran-3-yl)-ethoxy]-1H-indole-2-carboxylic acid 16o and amine 14.
Reaction SMILES: Br[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH:15]1([C:18]2[CH:22]=[C:21]([NH2:23])[NH:20][N:19]=2)[CH2:17][CH2:16]1>CCCCO>[CH:15]1([C:18]2[NH:19][N:20]=[C:21]([NH:23][C:2]3[C:7]([I:8])=[CH:6][N:5]=[C:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:3]=3)[CH:22]=2)[CH2:17][CH2:16]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Brc1nc(-c2ccccc2)ncc1I
Solvent: CCCCO
Product: Ic1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 64.1 %

Procedure:
To a solution of 4-bromo-5-iodo-2-phenylpyrimidine (1.18 g, 3.29 mmol, 1.0 equiv.) in n-BuOH (20 mL) was added 3-cyclopropyl-1H-pyrazol-5-amine (0.811 g, 6.58 mmol, 2 equ). After heating at 90° C. for 24 hours, the reaction was filtered to afford N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-iodo-2-phenylpyrimidin-4-amine (0.85 g, 88.7%). LC-MS (m/z): 404.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 0.74-0.77 (m, 2H), 0.98-1.02 (m, 2H), 1.96-2.01 (m, 1H), 6.40 (s, 2H), 7.50-7.54 (m, 3H), 8.27-8.30 (m, 2H), 8.63 (s, 1H), 8.88 (s, 2H), 12.32 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][NH:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH:27]([C:31](O)=[O:32])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH2:3]([N:4]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:31]([CH:27]1[O:28][CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26]1)=[O:32])[CH:2]([CH3:17])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: CC(C)CNCc1ccc2c(c1)OCCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc2c(c1)OCCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of 0.51 g (2.2 mmol) of 2-methyl-N-(2,3,4,5-tetrahydro-1-benzoxepin-8-ylmethyl)propan-1-amine, 0.51 g (2.2 mmol) of (±)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (Chem-Impex International), 0.59 g (4.4 mmol) of 1-hydroxybenzotriazole hydrate, 0.84 g (4.4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.71 mL (5.1 mmol) of triethylamine in 15 mL in dichloromethane was stirred overnight. The mixture was concentrated under reduced pressure, partitioned between 90 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate, and the layers were separated. The organic layer was washed with 30 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. Purification by flash chromatography (10-70% ethyl acetate in hexanes) gave 0.84 g (86%) of product as a solid white foam. MS (m+1)=447.4; H NMR (400 MHz, CDCl3) 7.09 (m, 1H), 6.8 (m, 2H), 4.7 (m, 1H), 4.44 (d, 1H, J 17 Hz), 4.2-3.8 (m, 6H), 3.50 (m, 1H), 3.21 (m, 2H), 3.02 (m, 2H), 2.79 (m, 2H), 1.96 (m, 3H), 1.72 (m, 2H), 1.45 (d, 9H, J 13 Hz), 0.85 (m, 6H).