Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[CH:4]=1.CN(C=O)C.[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CO>[CH3:24][O:25][C:26](=[O:29])[CH2:27][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:10]2[N:11]=[C:7]3[N:8]=[C:3]([NH2:2])[CH:4]=[CH:5][N:6]3[CH:9]=2)[CH:13]=1
Reactant: Nc1cc2nc(-c3cccc(O)c3)cn2cn1
Reactant: COC(=O)CBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(-c2cn3ccc(N)nc3n2)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
3-(7-Aminoimidazo[1,2-c]pyrimidin-2-yl)phenol hydrobromide (100 mg, 0.33 mmol) was combined with DMF (0.2 ml) to give a light brown suspension. Methyl-2-bromoacetate (55 mg, 0.36 mmol) and Cs2CO3 (424 mg, 1.3 mmol) were added, and the reaction mixture was stirred 2 h in a sealed tube at 65° C. The reaction mixture was directly put on a column and the product was isolated by flash chromatography (SiO2—NH2 cartridge; eluent: CH2Cl2/MeOH 95:05) to yield the title compound (57 mg, 58%) as a light yellow solid. MS (m/z)=299.1 [M+H+].
Reaction SMILES: [CH2:1]([C@:3]1([C:31]([O:33]C)=[O:32])[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:2].[OH-].[Na+].CO.Cl.C(N(CC)CC)C>C1COCC1>[CH2:1]([C@:3]1([C:31]([OH:33])=[O:32])[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH3:2]
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@]1(C(=O)O)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1

Procedure:
Methyl (1S,2R)-1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (315 mg, 0.653 mmol) was combined with aqueous 5M sodium hydroxide solution (0.65 mL, 3.3 mmol) in THF, with MeOH added to homogenize the mixture. This solution was stirred at 50° C. for 5d, after which triethylamine hydrochloride (540 mg, 3.9 mmol) was added. The heterogeneous mixture was concentrated, and chased twice with methanol and twice with benzene to give (1S,2R)-1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid as a white solid that was carried on without further purification. The solid was combined with BOP (349 mg, 0.790 mmol), hydroxylamine hydrochloride (100 mg, 1.43 mmol) and triethylamine (0.45 mL) in DMF (3 mL) and heated at 50° C. overnight. Additional BOP (362 mg, 0.819 mmol), hydroxylamine hydrochloride (150 mg, 2.1 mmol) and Et3N (0.3 mL) were then added and the reaction was stirred at 50° C. overnight. The reaction was still incomplete and more BOP (750 mg, 1.70 mmol), hydroxylamine hydrochloride (333 mg, 4.76 mol) and Et3N (0.6 mL) were added. After 5 h the reaction mixture was diluted with brine and extracted three times with ethyl acetate. The combined organic extracts were dried over Na2SO4, concentrated, and purified via HPLC, eluting with a gradient of 15-100% MeCN/H2O (10 min) to give (1S,2R)-N-hydroxy -1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (162 mg, 0.331 mmol, 51%) as a colorless solid. LCMS (M−H): 1.81 min, 483.8; 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 0.67 (t, J=7.45 Hz, 3H) 1.08-1.20 (m, 2H) 1.31-1.42 (m, 2H) 1.49-1.60 (m, 3H) 1.82-1.87 (m, 2H) 2.56-2.58 (m, 3H) 3.19-3.28 (m, 1H) 5.49-5.52 (m, 2H) 6.23 (d, J=8.59 Hz, 1H) 7.08-7.13 (m, 2H) 7.42 (s, 1H) 7.48 (td, J=7.64, 1.39 Hz, 1H) 7.64 (ddd, J=8.40, 6.88, 1.39 Hz, 1H) 7.70-7.75 (m, 2H) 7.91 (m, 2H).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C1N=C[N:19]([C:22](N2C=NC=C2)=[S:23])C=1>C1COCC1>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([C:22]([NH2:19])=[S:23])[CH2:5][CH2:4]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=S)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
Commercially available 4,4-difluoropiperidine hydrochloride (883 mg, 5.60 mmol) and triethylamine (0.85 mL, 6.10 mmol) were added to a solution of 1,1-thiocarbonyldiimidazole (1.05 g, 5.89 mmol) in THF (20 mL) under ice-cooling, followed by stirring at room temperature for 3 hr in an argon atmosphere. The reaction solution was concentrated. Concentrated aqueous ammonia (30 mL) was added to the residue, followed by stirring overnight at room temperature. The precipitated crystals were collected by filtration, washed with water, and dried to obtain 4,4-difluoropiperidinothiocarboxamide (850 mg, 4.72 mmol) as a light yellow powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:11])=[O:10]
Reactant: OCCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of 3,3,3-trifluoropropan-1-ol (500 mg, 4.38 mmol) in DCM (10 mL) was added TEA (1.22 mL, 8.77 mmol) followed by dropwise addition of methanesulfonyl chloride (0.51 mL, 6.58 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with DCM and the organic phase washed with brine, dried and concentrated to give crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (5:1) to give 3,3,3-trifluoropropyl methanesulfonate (490 mg, 58.2% yield) as light yellow oil. TLC (petroleum ether/ethyl acetate=3:1), Rf=0.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[N:47][CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[CH:48]=[N:47][CH:46]=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2cnccn2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnccn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-pyrazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.31 min; Mass spectrum (ESI+): m/z=525 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].C1CCN2C(=NCCC2)CC1>O1CCCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 70.6 %

Procedure:
A 20 ml microwave vial was charged with 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1, 3.06 mmol) and ethynyltrimethylsilane (902 mg, 9.18 mmol) in tetrahydrofuran (5 ml) to afford an orange solution. The reaction was purged with nitrogen before DBU (2.77 ml, 18.36 mmol), dichlorobis(triphenylphosphine)palladium(II) (107 mg, 0.153 mmol) and copper(I) iodide (58.3 mg, 0.306 mmol) were added and the whole was subjected to microwave radiation for 1 hour at 80° C. Upon cooling, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was purified by silica chromatography (eluting with 0-30% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-((trimethylsilyl)ethynyl)pyridazine (838 mg, 2.16 mmol, 70% yield)
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[F:30][C:31]1[CH:38]=[C:37]([CH:39]=[O:40])[CH:36]=[CH:35][C:32]=1[C:33]#[N:34]>C(Cl)Cl>[F:30][C:31]1[CH:38]=[C:37]([CH:39]([OH:40])[C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=2)[CH:36]=[CH:35][C:32]=1[C:33]#[N:34]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 4-iodo-1-trityl-1H-imidazole (5.00 g, 11.5 mmol) in anhydrous CH2Cl2 (30 mL) was added a 3.0M solution of ethylmagnesium bromide (6.58 mL, 19.7 mmol) with stirring under Ar. After 3 h, the reaction mixture was cooled to −78° C. and a solution of 2-fluoro-4-formyl-benzonitrile (as described in Step A above) (1.70 g, 11.5 mmol) dissolved in CH2Cl2 (20 mL) was added dropwise. The reaction was allowed to warm to RT over 2 h, quenched with saturated NH4Cl solution, diluted with satd. NaHCO3 solution to pH=8.5, and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), concentrated and purified using SiO2 chromatography (0-1% MeOH/CH2Cl2) to yield the title compound.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]1([NH:12][C:13](=[O:24])[CH2:14][CH2:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][CH2:14][C:13]([NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:24])=[S:4]
Reactant: NNC(N)=S
Reactant: O=C(CCC(=O)c1ccccc1)NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCC(=O)NC1CCCCC1)c1ccccc1
Yield: 69.2 %

Procedure:
Thiosemicarbazide (1.75 g, 19.2 mmol) was added to a solution of N-cyclohexyl-4-oxo-4-phenyl-butyramide (3.30 g, 11.7 mmol), prepared in the previous step, in 40 ml of methanol plus 3.2 ml of 1 N HCl plus 3.2 ml of water and the reaction stirred at room temperature for 21 hours. The solid formed was removed by filtration and dried to give 2.69 g of a white solid. The filtrate was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, wash ed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 1.10 g of a white foam. The initial solid filtered from the reaction was dissolved in methylene chloride, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a white foam. Both materials were combined and crystallized from methylene chloride-ethyl acetate to give the title compound (3.31 g, 69%) as a white solid, mp 89-92° C.
Reaction SMILES: [H-].[Na+].O=C1CCCN1.Cl[CH2:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[C:21]([C:22](=[O:28])[C:23]2[S:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:14].O>C1(C)C=CC=CC=1>[O:14]=[C:13]1[CH2:12][CH2:11][CH2:10][N:15]1[C:16]1[C:21]([C:22](=[O:28])[C:23]2[S:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(CCCCl)Nc1ncccc1C(=O)c1cccs1
Agent: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1cccs1)c1cccnc1N1CCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 20 ml of toluene is suspended 0.6 g of 60% sodium hydride, whereto 3 ml of 2-oxopyrrolidine is added. Under ice-cooling, 2.7 g of 2-(4-chlorobutyrylamino)-3-(2-thenoyl)pyridine is added thereto, and the mixture is stirred at room temperature for 1 hour. The mixture is poured into water, and the solvent of the toluene layer is distilled off. The residue is recrystallized from toluene-isopropyl ether to give 2-(2-oxopyrrolidin-1-yl)-3-(2-thenoyl)pyridine, m.p. 148°-150° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:15])[CH2:4]1)=O.[C:31]1([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>>[C:31]1([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:12]=[CH:11][S:10][CH:9]=4)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]4[CH2:30][CH2:29][CH2:28]4)[C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[O:15])[CH2:4]3)[CH2:44][CH2:45]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccsc3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](CN3CCC(CCCc4ccccc4)CC3)[C@@H](c3ccsc3)C2)cc1
Yield: 89.8 %

Procedure:
The title compound was prepared from 20 mg (0.046 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 87, Step F) and 12.9 mg (0.046 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedure analogous to that described in EXAMPLE 1, Step J to provide 25.4 mg (88%) of the title compound: RF: 0.47 (3:2 v/v hexanes/EtOAc); 1H NMR (300 Mhz) δ 1.10-3.22 (m, 3H), 3.80 (s, 3H), 5.07 (ABq, J=11.9,2H), 6.85-6.93 (m, 4H), 7.14-7.33 (m, 8H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.C(OCC)C>COCCOCCOC>[C:10]1([NH:9][C:2]2[N:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cc(Cl)ncn1
Reactant: Nc1ccccc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: Oc1cc(Nc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
6-Chloropyrimidin-4-ol (500 mg, 3.85 mmol), aniline (420 μL, 4.62 mmol) and N,N-diisopropylethylamine (1 mL) in diethylene glycol dimethyl ether (5 mL) was heated to 120° C. and stirred for 8 h. The mixture was cooled to room temperature then diluted with actone:diethyl ether solution (1:1, 15 ml) to give a precipitate. The solid collected by filtration and washed with acetone then dried to afford 6-(phenylamino)pyrimidin-4-ol (255 mg, 35.5%). MS (EI) for C10H9N3O: 188.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[S:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].[C:29]([C:33]1[CH:37]=[C:36]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[O:35][N:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[S:21][C:22]1[CH:23]=[C:24]([NH:25][C:39]([NH:38][C:36]2[O:35][N:34]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:37]=2)=[O:40])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OCCOC
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c2cc1OCCOC
Yield: 52 %

Procedure:
The title compound was prepared as described in Example 113C by using compound 3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)aniline (138 mg, 0.34 mmol) and phenyl 3-tert-butylisoxazol-5-ylcarbamate described in Example 132A (116 mg, 0.45 mmol) to give 1-(3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)-3-(3-tert-butylisoxazol-5-yl)urea (100 mg, 52%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.05 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.46 (d, 1H), 7.45-7.38 (m, 3H), 7.31 (d, 1H), 6.05 (s, 1H), 4.36-4.32 (m, 4H), 3.79-3.76 (m, 4H), 3.37 (s, 6H), 1.24 (s, 9H); LC-MS (ESI) m/z 568 (M+H)+.
Reaction SMILES: [C:1](/[C:4](/[CH3:31])=[CH:5]/[C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:28][CH2:29][CH3:30])=[CH:11][N:12]2[CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:8][CH:7]=1)([OH:3])=[O:2]>[Pd].O1CCCC1>[C:1]([CH:4]([CH3:31])[CH2:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:28][CH2:29][CH3:30])=[CH:11][N:12]2[CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: CCCc1cn(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)O)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cn(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)O)ccc12
Yield: 96.9 %

Procedure:
Methyl E-4-[6-(2-carboxyprop-1-enyl)-3-propylindol-1-ylmethyl]-3-methoxybenzoate (1.15 g) with palladium on carbon (10% w/w, 0.2 g) in dry tetrahydrofuran (50 ml) was hydrogenated at 2.0 bar. The mixture was filtered through a pad of diatomaceous earth and evaporated to give methyl 4-[6-(2-carboxypropyl)-3-propylindol-1-ylmethyl]-3-methoxybenzoate (1.12 g, 97%) as an oil; partial NMR (300 MHz, DMSO-d6): 0.93(t, 3H, CH2CH3), 0.98(d, 3H, CH(CH3)), 1.63(m, 2H, CH2CH3), 2.60(m, 4H, CH2CH2CH3, CHCH2), 2.96(m, 1H, CH(CH3)), 3.82(s, 3H, OCH3), 3.95(s, 3H, OCH3), 5.31(s, 2H, NCH2).
Reaction SMILES: C([NH:4][C:5]1[C:6](=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=O)C.Cl>O1CCOCC1>[Br:14][C:11]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:4])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(Br)cc1C(=O)O
Temperature: 110 °C
Yield: 91.7 %

Procedure:
To a mixture of 9 (71 g, 0.275 mol) in 1,4-dioxane (400 mL) was added HCl (400 mL). The mixture was refluxed for 4 h at 110° C. Then the mixture was concentrated and added to 300 mL water. The mixture was filtered and the pH was adjusted to 6 with 2N NaOH, washed with water and dried to give 10 as a white solid (54.5 g, yield: 91.7%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10]C#N)=[C:4]([F:13])[CH:3]=1.[Br:14]C1C=CC(C2(C#N)CC2)=C(F)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([CH2:10][Br:14])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: N#CC1(c2ccc(Br)cc2F)CC1
Reactant: COc1cc(CC#N)c(F)cc1Br
Product: COc1cc(CBr)c(F)cc1Br

Procedure:
The desired product was prepared analogously to Example A (141) step 1, substituting (4-Bromo-2-fluoro-5-methoxy-phenyl)-acetonitrile (1.95 g, 8.0 mmol) from step 3 below in place of 1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 2.45 g, 82.2%. 1H NMR (CDCl3) δ: 3.82 (s, 3H), 4.40 (s, 2H), 6.82 (d, J=5.8 Hz, 1H), 7.24 (d, J=10.58 Hz, 1H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[N+:12]([C:15]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:16]=1[CH:17]=O)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:16]=1[CH:17]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11])([O-:14])=[O:13]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: O=C1CCc2ccccc2C1
Product: COc1cc(C=C2C(=O)CCc3ccccc32)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 2-tetralone and 2-nitro-4,5-dimethoxybenzaldehyde; mp 58-60° C.; IR (Nujol): 1724, 1540; 1H NMR: δ2.71 (2H, t), 3.08 (2H t), 3.56 (3H, s), 4.02 (3H, s), 6.51 (1H, s), 6.92-6.96 (2H, m), 7.17-7.24 (2H, m), 7.73 (1H, s), 8.00 (1H, s); 13C NMR: δ28.3, 27.8, 56.7, 56.9, 108.3, 112.5, 126.7, 127.6, 128.5, 128.8, 129.9, 132.3, 133.4, 134.5, 138.8, 141.6, 149.4, 153.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[C:14](=[O:15])[O:13][C:12]([CH3:17])([CH3:16])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[C:19]([Mg]Br)([CH3:21])=[CH2:20].OC1C=C(C(C2C(=O)OC(C)(C)OC2=O)CC=C)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:9]2[C:10](=[O:18])[O:11][C:12]([CH3:16])([CH3:17])[O:13][C:14]2=[O:15])[C:19]([CH3:21])=[CH2:20])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[Mg]Br
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Agent: C=CCC(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Product: C=C(C)C(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Yield: 37.4 %

Procedure:
Compound 8.1 (2.00 g, 8.1 mmol) was treated with isopropenylmagnesium bromide (available from Aldrich) (0.5 M in THF) (97 mL, 48 mmol) according to the method described for preparation of 43.1 to afford 48.1 (0.88 g, 38%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=2)[O:8][CH:7]([CH3:9])[CH2:6][NH:5][CH2:4]1)[CH3:2]>Br>[CH2:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[O:8][CH:7]([CH3:9])[CH2:6][NH:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CNCC(C)O1
Agent: Br
Product: CCC1(c2cccc(O)c2)CNCC(C)O1
Yield: 113.2 %

Procedure:
2-Ethyl-2-(3-methoxyphenyl)-6-methylmorpholine (2.63 g) was refluxed with aq 48% HBr (20 ml) for 2.5 h. The residue on evaporation was re-evaporated from isopropyl alcohol several times, giving ultimately a green gum (2.8 g), which was dissolved in methanol and basified with 0.880 ammonia. The methanol and ammonia were evaporated under reduced pressure and the aqueous remaining was shaken with chloroform (2×100 ml). The chloroform layers were washed and dried and evaporated, leaving an orange oil (8.4 g) that crystallised from ethyl acetate (25 ml). The yellow hygroscopic solid was dissolved in isopropyl alcohol (15 ml) and acidified with ethereal hydrogen chloride. On cooling crystals of the title compound hydrochloride were obtained (0.85 g, mp 200°-205° C.). Gas-liquid chromatography revealed the isomer ratio to be 20:1.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([CH:17]([OH:19])[CH3:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[C:3]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(O)c1cc(F)c(OCc2ccccc2)c(F)c1OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(F)c(OCc2ccccc2)c(F)c1OCc1ccccc1

Procedure:
A 1.0M solution of Compound 24 in CH2Cl2 is added to a suspension of pyridinium chlorochromate (4.0 eq) in CH2Cl2 at 20° C. with stirring. The reaction is stirred for 24 hours and filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo and then purified by silica gel column chromatography (eluted with Hex/EtOAc) to yield Compound 25.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Br:18])=[N:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)=[O:7])C.Cl>C1COCC1>[Br:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[N:15]=2)[N:10]=[CH:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2ncc(C(=O)O)c(Br)c2n1
Reaction time: 8 h

Procedure:
2 N NaOH (300 mL, 600 mmol) was added dropwise over 30 min to a stirred solution of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (83.56 g, 268 mmol) in THF (835 mL). Stirring was continued overnight, at which time LC/MS showed that the saponification was complete. 2 N HCl was added to pH 6 and the THF was removed in vacuo. 2 N HCl was added to pH 2, then water (250 mL) was added, and the mixture was cooled thoroughly in ice. The solid was collected by suction filtration, washed with water and dried (first using a rotary evaporator at 50° C. and then under high vacuum at 50° C. overnight) to give the title compound (76.7 g, slightly over quantitative). This material was used without further purification.