Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1([CH2:26]CO)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(C)C(C)=CC=CC=1.[OH-].[Na+]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].C1(C)C=CC=CC=1>[C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH2:19][CH2:26][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2cc(-c3ccccc3)oc12
Reactant: OCCN1CCCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCCCC1)c1cccc2cc(-c3ccccc3)oc12
Yield: 95.9 %

Procedure:
A mixture of 0.76 g of methyl 2-phenylbenzofuran-7-carboxylate, 0.46 g of 2-piperidinoethanol, 0.05 g of tetraisopropyl orthotitanate and 5 ml of xylene is refluxed for 4 hours. Toluene and an aqueous 10% sodium hydroxide solution are added to the reaction mixture and the mixture is filtered. The filtrate is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1) to give 1.01 g of 2-piperidinoethyl 2-phenylbenzofuran-7-carboxylate as pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N:26]2[CH2:31][CH2:30][N:29]([C@@H:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])[CH2:28][CH2:27]2)[C:17]1=[O:40])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[S:52](Cl)(=[O:54])=[O:53]>ClCCl>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:5]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[N:26]3[CH2:31][CH2:30][N:29]([C@@H:32]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH3:33])[CH2:28][CH2:27]3)[C:17]2=[O:40])[CH2:4][CH2:3][CH2:2][NH:1][S:52]([C:48]2[S:47][CH:51]=[CH:50][CH:49]=2)(=[O:54])=[O:53])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(C(CCCN)N2C(=O)c3cccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(C(CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.6 %

Procedure:
A 10-mL round bottom flask was charge with Compound 66 (20.0 mg, 0.04 mmol), potassium carbonate (8.0 mg, 0.06 mmol), and dichloromethane (0.5 mL). Thiophene-2-sulfonyl chloride (8.0 mg, 0.04 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and purified via flash chromatography (230-400 mesh silica gel 60, gradient 100:0-95:5 CH2Cl2:methanol) to give 9.8 mg of Compound 68 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.71-7.74 (m, 1 H), 7.51-7.61 (m, 3 H), 7.29-7.38 (m, 6 H), 7.02-7.18 (m, 3 H), 6.73-6.80 (m, 1 H), 5.10-5.17 (m, 1 H), 4.50-4.57 (m, 1 H), 3.86 (s, 3 H), 3.83 (s, 3 H), 3.31-3.39 (m, 4 H), 3.06-3.11 (m, 4 H), 2.65-2.74 (m, 2 H), 2.45-2.55 (m, 1 H), 2.20-2.31 (m, 1 H), 1.58-1.63 (m, 2 H), and 1.49 (d, J=6.8 Hz, 3 H); MS (ES+) 689 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH:45]1[CH2:49][CH2:48][N:47]=[C:46]1[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH:57][CH3:58])=[CH:52][CH:51]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:57]([CH2:56][C:53]3[CH:54]=[CH:55][C:50]([C:46]4[NH:47][CH2:48][CH2:49][N:45]=4)=[CH:51][CH:52]=3)[CH3:58])=[O:22])[CH:16]=2)[CH3:13])(=[O:10])=[O:11])=[C:4]([Cl:23])[CH:3]=1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Reactant: CNCc1ccc(C2=NCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2c(Cl)cc(Br)cc2Cl)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-({[(4-bromo-2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.14 mmol), EDCI (33 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol) in DMF (0.5 mL) was added a solution of 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (28 mg, 0.13 mmol) and DIPEA (0.025 mL, 0.14 mmol) in DMF (0.5 mL). The reaction was heated to 60° C. for 5 h, then concentrated and diluted with DCM. The solution was washed with saturated aqueous NH4Cl(2×2 mL) and saturated brine (2 mL), and dried over MgSO4. The filtrate was shaken with Ambersep resin for 48 h, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:25])[CH:9]=[C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S)C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]1([NH:7][C:8](=[O:25])[CH2:9][CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C=C(Sc1ccccc1)Sc1ccccc1)Nc1ccccc1
Agent: Sc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CC(Sc1ccccc1)Sc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 146.2 %

Procedure:
To N-phenyl-3,3-bis(phenylthio)acrylamide (2.04 g) were added thiophenol (8.21 mL) and triethylamine (1.12 mL), and the mixture was stirred at room temperature for 11 hours. To the reaction mixture was added ethyl acetate (50 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was isolated and purified by medium pressure preparative liquid chromatography (YAMAZEN SI-40C, hexane:ethyl acetate=85:15) to obtain N-phenyl-3,3-bis(phenylthio)propionamide (3.00 g) as an orange oil.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[Cl:41][C:42]1[CH:47]=[C:46]([NH:48][CH2:49][C:50]2[O:51][CH:52]=[CH:53][CH:54]=2)[C:45]([C:55]([O:57][CH2:58][C:59]([Cl:62])([Cl:61])[Cl:60])=[O:56])=[CH:44][C:43]=1[S:63]([NH:66][CH2:67][O:68][C:69](=[O:79])[CH2:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:77]Cl)=[O:75])(=[O:65])=[O:64]>C(#N)C>[Cl:41][C:42]1[CH:47]=[C:46]([NH:48][CH2:49][C:50]2[O:51][CH:52]=[CH:53][CH:54]=2)[C:45]([C:55]([O:57][CH2:58][C:59]([Cl:60])([Cl:62])[Cl:61])=[O:56])=[CH:44][C:43]=1[S:63]([NH:66][CH2:67][O:68][C:69](=[O:79])[CH2:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:77][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:75])(=[O:65])=[O:64]
Reactant: O=C(CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)OCCl
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride, (700) (U.S. Pat. No. 3,819,706; U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) are stirred with cooling on an ice bath. A solution of chloromethyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles are removed by spin evaporation, and the residue is partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that is recrystallized to give 2-[(6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone. See U.S. Pat. No. 5,104,870; Sandler et al., Organic Functional Group Preparations, (1968) p. 324.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OC([N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26]OS1(=O)=O)=O)(C)(C)C>>[NH2:23][C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Reactant: COC(=O)COc1ccc2[nH]ccc2c1
Product: COC(=O)COc1ccc2c(ccn2CCC(C)(C)N)c1

Procedure:
Prepared analogously to Component V by alkylation of methyl (1H-indol-5-yloxy)-acetate with N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinane-2,2-dioxide and subsequent cleaving of the acid protecting group.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[C:19](OCC)=[O:20])[C:3]=1[O:26][CH2:27][CH3:28].[H-].C([Al+]CC(C)C)C(C)C>>[Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[CH2:19][OH:20])[C:3]=1[O:26][CH2:27][CH3:28]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Cl)c1OCC)C(C)(C)CC=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1c(/C(C)=C(/F)CO)cc2c(c1Cl)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure G-1, ethyl (2E)-3-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-but-2-enoate (Compound A-133, 0.27 g, 0.66 mmol) and diisobutylaluminum hydride (1M in methylene chloride, 2.64 mL, 2.64 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% to 15% ethyl acetate in hexanes).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.Cl.[N:15](OCCC(C)C)=[O:16]>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N:15]=[O:16]
Reactant: CC(C)CCON=O
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Agent: Cl
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(N)c1N=O
Reaction time: 4 h

Procedure:
To a solution of 17.3 g (0.1 mol) of 5-amino-3-methyl-1-phenylpyrazole in 200 cm3 of absolute ethanol were added dropwise 0.5 cm3 of 12 N hydrochloric acid and then 13.5 cm3 of isoamyl nitrite, at 0° C. The solution was then warmed to and left at room temperature for 4 hours. An orange-coloured solid crystallized out. This solid was filtered off on a sinter funnel and washed with 100 cm3 of isopropyl ether. After drying under vacuum at room temperature, 17 g of 5-amino-3-methyl-4-nitroso-1-phenylpyrazole were obtained in the form of an orange-coloured solid, the melting point of which was from 202 to 204° C.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1.CC(O)=O>CC(O)C>[Br:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([S:40](=[O:42])(=[O:41])[NH2:43])=[CH:36][CH:35]=3)=[N:15]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Cl)nc23)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc23)CC1
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 36.9 %

Procedure:
Solid KOtBu (442 mg, 3.95 mmole) was added to a solution of tert-butyl 4-(7-bromo-2-chloroquinazolin-8-yloxy)piperidine-1-carboxylate (500 mg, 1.13 mmole) and 4-aminobenzenesulfonamide (777 mg, 4.62 mmole) in IPA (15 mL). The reaction was sealed and heated to 105° C. with stirring. After 2.5 hours, AcOH was added to the reaction to pH 4 and the reaction was evaporated to a solid. The crude product was dissolved in DMSO (15 mL) and purified by prep. HPLC to give 241 mg of product in 37% yield (417 mmole).
Reaction SMILES: [CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([C:18](=O)[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([C:18](=[N:26][OH:27])[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=O)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=NO)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
After 5.45 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone (12) (17 mmol) was dispersed in 50 ml of ethanol and 1.42 g of hydroxylamine hydrochloride (20.4 mmol) and 1.67 g of sodium acetate (20.4 mmol) were added thereto, the reaction mixture was slowly heated and refluxed for 1 hour. The reaction mixture was cooled to room temperature, and 100 ml of distilled water was added thereto and stirred for about 30 minutes. Then, the product was extracted with 200 ml of ethylacetate and sequentially washed with saturated aqueous sodium bicarbonate solution and 100 ml of distilled water, and the recovered organic layer was dried over anhydrous magnesium sulfate, followed by distilling the solvent under reduced pressure. The obtained solid product was dried, thereby obtaining 4.97 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone oxime (13) (87.3%) as a light yellow product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])=[CH:11][C:10]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][C:35]1([CH3:42])[CH2:40][C:39](=[O:41])[O:38][C:36]1=[O:37]>C1COCC1.CCOCC>[C:30]([C:10]1[CH:11]=[C:12]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)=[O:15])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:41])[CH2:40][C:35]([CH3:42])([CH3:34])[C:36]([OH:38])=[O:37])=[CH:3][CH:4]=2)[N:9]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(N)cc2)n1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CC(=O)Nc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1)C(=O)O
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A solution of 1-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea (208 mg, 0.47 mmol) and 2,2-dimethylsuccinic anhydride (66 mg, 0.52 mmol, 1.1 eq) in 2 mL THF was stirred at room temperature overnight. HPLC analysis indicated that starting material was remaining. The reaction was then heated at 60° C. for 2 days, at which time HPLC analysis indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the resulting suspension was diluted with Et2O. The solid was isolated by filtration to afford the desired product (227 mg, 85%). 1H-NMR (DMSO-d6) δ 12.06 (s, 1H), 10.06 (s, 1H), 9.09 (s, 1H), 8.40 (d, J=6.0 Hz, 2H), 8.31 (s, 1H), 7.69 (d, J=9.0 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 6.85 (dd, J=1.5 & 4.7 Hz, 2H), 6.33 (s, 1H), 2.59 (s, 2H), 1.26 (s, 9H), 1.21 (s, 6H); MS LC-MS [M+H]+=571.3, RT=2.49 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:25]4[CH2:28][CH2:27][CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NC1CCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and cyclobutylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 2H) 1.95-2.09 (m, 2H) 2.11-2.24 (m, 2H) 2.36 (s, 3H) 4.28-4.48 (m, 1H) 7.59 (dd, J=8.08, 1.52 Hz, 1H) 7.66 (s, 1H) 7.70 (br. s., 1H) 8.10 (br. s., 1H) 8.35 (d, J=6.57 Hz, 2H) 8.78 (d, J=7.33 Hz, 1H) 8.81-8.91 (m, 1H) 13.12 (br. s., 1H). MS m/z [M+H]+ 374.2
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[C:3]1=[O:24].[ClH:26]>CCOC(C)=O>[ClH:26].[CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:3]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)c3nccnc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Temperature: 25 °C

Procedure:
To a stirred cooled (0° C.) solution of tert-butyl 4-(7,7-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate (0.700 g, 2.021 mmol) in EtOAc (15 mL) was added hydrogen chloride (2.53 ml, 10.10 mmol). The mixture was then stirred at room temperature over the weekend, concentrated to dryness and used in the next step (570 mg, 100%). MS (M+1): 283.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17](N1C=CN=C1)([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:18]>C(Cl)Cl>[C:9]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:18])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(F)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(F)ccc1NC(=O)n1ccnc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a solution of (2-amino-5-fluorophenyl)(phenyl)methanone (6.60 g, 30.67 mmol) in CH2Cl2 (60 mL) was added carbonyldiimidazole (6.96 g, 42.93 mmol). The reaction was heated to 45° C. After 16 h at 45° C., the reaction was cooled to ambient temperature and the precipitate isolated by vacuum filtration and washed with fresh CH2Cl2 to give N-(2-benzoyl-4-fluorophenyl)-1H-imidazole-1-carboxamide as a white solid. 1H NMR (CDCl3, 400 MHz) 8.91 (s, NH); 7.47 (m, 3H, ArH); 7.25 (m, 1H, ArH); 7.18 (m, 4H, ArH); 6.99 (m, 1H, ArH); 6.95 (s, 1H, ArH); 6.53 (m, 1H, ArH); MS (Electrospray): m/z 332.1 (M+Na).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:21])=[CH:18][C:19]=1[OH:20])=[O:13].C([O:24][C:25](=O)[C:26]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[C:28]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:27]=1)C.Cl>O1CCCC1>[CH2:41]([O:40][C:28]1[CH:27]=[C:26]([C:25](=[O:24])[CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:21])=[CH:18][C:19]=2[OH:20])=[O:13])[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(O)cc1O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (217.5 mL, 260 mmol) was added to a well-stirred solution of 2,4-dihydroxy acetophenone, 14 (9.88 g, 65 mmol) in tetrahydrofuran (150 mL) under nitrogen atmosphere at −78° C. for 30 min. The reaction mixture was stirred at −78° C. for 1 h and at −30° C. for 2 h. It was again cooled to −78° C. and a solution of ethyl-3,5-dibenzyloxy-benzoate 8 (23.5 g, 65 mmol) in tetrahydrofuran (100 mL) was added over a period of 30 min. It was further stirred at room temperature for overnight and poured into ice water containing hydrochloric acid. It was extracted with chloroform, dried over sodium sulphate, filtered and evaporated on rotavapor to afford 1-(3,5-bis-benzyloxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (16). The residue, 16 (37.8 g) was refluxed with Dowex-H+ (8 g) in 2-propanol (300 mL) for 3-4 h. 2-Propanol was evaporated on rotavapor, residue suspended in hot dimethyl formamide and filtered. The filtrate was concentrated under reduced pressure and the product was washed with cooled methanol (3*200 mL) to afford 22. Yield 23.8 g (81%); mp 248-249° C.; MS (FAB) 451 (M++1); IR (KBr) 3452, 1620; 1H NMR (200 MHz, DMSO-d6) δ 7.84 (d, J=8.7 Hz, 1H), 7.52-7.28 (m, 10H), 7.23 (d, J=1.9 Hz, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.89 (s, 1H), 6.89 (dd, J=8.6 Hz, 2.1 Hz, 1H), 6.82 (s, 1H), 5.14 (s, 4H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:3].C[Si](C)(C)[N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>C1C=CC=CC=1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[O:3])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Solvent: c1ccccc1
Product: O=C1CCCN1C(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a solution of 4-bromophenyl chloroformate (4.19 g, 20.0 mmol) in anhydrous benzene (20 ml) was added a solution of 1-trimethylsilyl-2-pyrrolidinone (3.46 g, 22.0 mmol) in anhydrous benzene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. Recrystallization from 2-propanol afforded 3.00 g of colorless prisms. Yield 53%
Reaction SMILES: [NH2:1][C@H:2]1[CH2:9][CH:8]=[CH:7][CH2:6]C[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17].C(N)C=C>>[NH2:1][C@H:2]1[CH2:9][CH:8]=[CH:7][CH2:6][N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17]
Reactant: N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Agent: N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Solvent: C=CCN
Product: N[C@H]1CC=CCN(Cc2ccccc2)C1=O

Procedure:
(S,Z)-3-Amino-1-benzyl-3,4-dihydro-1H-azepin-2(7H)-one (6.15 mg, 0.028 mmol) was synthesized as described for the preparation of Intermediate 44 using prop-2-en-1-amine in step A. Anal. Calcd. for C13H16N2O m/z 216.2. found: 217.0 (M+H)+.