Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:19]=[C:18]4[CH2:20][O:21][C:22]5[CH:53]=[C:52]6[C:25]([CH:26]=[CH:27][C:28]7[N:32]=[C:31]([C@@H:33]8[CH2:37][CH2:36][CH2:35][N:34]8[C:38](=[O:51])[C@H:39]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:40]8[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=8)[NH:30][C:29]=76)=[CH:24][C:23]=5[C:17]4=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:54][O:55][C@H:56]([CH3:66])[C@H:57]([NH:61][C:62]([O:64][CH3:65])=[O:63])[C:58](O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:65][O:64][C:62]([NH:61][C@H:57]([C:58]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]3[CH2:20][O:21][C:22]4[CH:53]=[C:52]5[C:25]([CH:26]=[CH:27][C:28]6[N:32]=[C:31]([C@@H:33]7[CH2:37][CH2:36][CH2:35][N:34]7[C:38](=[O:51])[C@H:39]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:40]7[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=7)[NH:30][C:29]=65)=[CH:24][C:23]=4[C:17]3=[CH:16][CH:15]=2)=[CH:12][N:13]=1)=[O:59])[C@@H:56]([CH3:66])[O:55][CH3:54])=[O:63]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl {(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (51 mg, 0.072 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (14 mg, 0.072 mmol), HATU (30 mg, 0.079 mmol) and 0.4 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. The product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate. The eluent was concentrated, taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (24 mg)
Reaction SMILES: [N:1]1([CH:6]=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][C:10]#N)CCCC1.[ClH:14]>>[Cl:14][C:10]1[CH:9]=[CH:8][C:7]([C:6]#[N:1])=[CH:12][N:13]=1
Reactant: N#CC=CC(C#N)=CN1CCCC1
Reactant: Cl
Product: N#Cc1ccc(Cl)nc1

Procedure:
Analogously to Example 5, pyrrolidinomethylene-glutacononitrile was cyclized with HCl gas. 2-Chloro-5-cyanopyridine was obtained in 83.3% of the theoretical yield.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>CN(C=O)C>[CH2:9]([O:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(OCc5ccccc5)nc34)cc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
NaH (60% in mineral oil; 0.071 g, 1.763 mmol) was suspended in 1 mL DMF. Phenylmethanol (0.183 ml, 1.763 mmol) was added slowly dropwise. After 10 min, 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added, and the reaction was heated to 100° C. for 30 min. The mixture was cooled and partitioned between saturated aq. NH4Cl and DCM. The aq. layer was extracted with DCM (3×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-100% 90/10 DCM/MeOH in DCM The product-containing fractions were concentrated to afford 2-(2-(benzyloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.018 g, 0.049 mmol, 19% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (1H, br. s), 8.32 (1H, d, J=9.0 Hz), 8.00 (1H, dt, J=7.2, 1.0 Hz), 7.76 (1H, dt, J=7.9, 0.8 Hz), 7.26-7.59 (6H, m), 7.10-7.22 (2H, m), 6.87-6.99 (1H, m), 5.62 (2H, s), 3.36-3.51 (2H, m), 2.86 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 370.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[C:18]=1[CH3:19].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[C:21]([C:23]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:24])[N:22]=2)[C:18]=1[CH3:19]
Reactant: CCOC(=O)c1nc2ccc(I)c(C)n2c1-c1ccccn1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1c(I)ccc2nc(C(=O)Nc3ccccc3)c(-c3ccccn3)n12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 852 μL of aniline in 104 mL of toluene cooled to 0° C. are added dropwise 6.2 mL of a 2M solution of trimethylaluminium in toluene, followed by addition, at 20° C., of 1.5 g of ethyl 6-iodo-5-methyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate. The reaction mixture is stirred for 2 hours at 20° C. The resulting mixture is cooled to 4° C. and 120 mL of saturated ammonium chloride solution are then added. After concentrating under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate, filtered through Celite and evaporated to dryness under reduced pressure. The residue is triturated in methanol, filtered off and dried to give 1.15 g of 6-iodo-5-methyl-N-phenyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a yellow solid.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[OH-:10].[Na+:11].C>O>[Na+:11].[CH2:1]([P:3]([OH:4])([CH2:6][CH2:7][C:8]([O-:10])=[O:9])=[O:5])[CH3:2]
Reactant: [OH-]
Reactant: CCP(=O)(O)CCCO
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC(=O)[O-]
Temperature: 70 °C
Yield: 93 %

Procedure:
15.2 g (0.1 mol) of ethyl-3-hydroxypropylphosphinic acid (produced as in Example 5) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.45 g of charcoal with 5% Pt and 1% Bi is added, the suspension is heated to 70° C. and air is passed through the suspension at 10 l/h. All the while, the pH of the suspension is maintained at pH=9 by adding 2N NaOH in solution. After the reaction is ended, the reaction solution is filtered to remove the catalyst, the filter residue is washed and the water is distilled off in vacuo to obtain 19.5 g (93% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid sodium salt as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([CH2:25][C:26](O)=[O:27])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:44]([O:46][C:47](=[O:53])[CH2:48][C@@H:49]([C:51]#[CH:52])[NH2:50])[CH3:45].CCN(CC)CC>>[CH2:44]([O:46][C:47](=[O:53])[CH2:48][C@@H:49]([C:51]#[CH:52])[NH:50][C:26](=[O:27])[CH2:25][N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[C:21]1=[O:24])[CH3:45]
Reactant: C#C[C@@H](N)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)CC3)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C#C[C@H](CC(=O)OCC)NC(=O)CN1CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-5 (150 mg, 0.39 mmol), HOBT (63 mg, 0.46 mmol) and EDC (111 mg, 0.58 mmol) was added 3(S)-(ethynyl)-β-alanine ethyl ester hydrochloride (1-32) (U.S. Pat. No. 5,272,162; 82 mg, 0.46 mmol) and Et3N (80.7 gl, 0.58 mmol). The mixture was stirred at room temperature under argon for 16 hours and then partitioned between EtOAc and 10% citric acid. The aqueous phase was extracted with EtOAc (x3) and the combined organic layers then washed with saturated aqueous NaHCO3 followed by brine. Removal of the dried (MgSO4) solvent afforded a yellow oil which was purified by column chromatography (silica gel; hexane/EtOAc 1:1) to give 1-33 as an oil. Rf (silica; EtOAc/hexane 2:1) 0.57 ##STR51##
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH2:27]>C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH:27][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: O[C@H](CNCc1ccc(Cl)c(Cl)c1)COc1ccc(-c2noc3cc(F)ccc23)cc1
Yield: 78.9 %

Procedure:
Combine (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (29) (250 mg, 0.86 mmol), 3,4-dichlorobenzylamine (617 mg, 3.50 mmol), ethanol (4.0 ml) and heat (˜80° C.) for 16 hours. Cool reaction at 0° C. for 1 h. Collect the solid product and wash with cold ethanol several times. Dry the solid at (50° C./0.5 mm Hg) overnight to give 313 mg (77% yield) of the title compound. Purity by LC/MS=96%, [M+H]+=461.
Reaction SMILES: [C:1]1([C:7]2[CH:21]=[C:10]3[C:11]4[CH:17]([CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][C:12]=4[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([C:7]2[CH:21]=[C:10]3[C:11]4[CH:17]([CH2:18][CH2:19][NH:20][C:29](=[O:31])[CH3:30])[CH2:16][CH2:15][C:12]=4[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCC1CCc2ccn3nc(-c4ccccc4)cc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1CCc2ccn3nc(-c4ccccc4)cc3c21
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
2-(2-Phenyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine (200 mg, 0.721 mmol) was dissolved in tetrahydrofuran (7 mL), triethylamine (201 μL, 1.44 mmol) and acetic anhydride (81.8 μL, 0.865 mmol) were added under ice-cooling, and the mixture was stirred for 15 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (195 mg, total yield from Reference Example 65, 69%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2oc(C)nc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc2cc(CBr)ccc2o1
Temperature: 25 °C

Procedure:
A mixture of commercially available 2,5-dimethylbenzo[d]oxazole (1.000 g; 6.79 mmol), N-bromosuccinimide (1.209 g; 6.79 mmol), and commercially available dibenzoyl peroxide (11 mg; 0.046 mmol) in anh. CCl4 (10 ml) was refluxed, under nitrogen, for 17 h. After cooling to rt, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=9/1) afforded 5-(bromomethyl)-2-methylbenzo[d]oxazole as a yellow solid. LC-MS (conditions E): tR=0.61 min.; [M+H]+: 226.12 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1ccc(N)cn1
Solvent: CC(=O)O
Product: CCCc1ccc(NC(C)=O)cn1
Yield: 80.1 %

Procedure:
A mixture of 5-amino-2-n-propylpyridine (example 23, step2) (62.7 g, 0.46 mol) and 45.7 g (0.483 mol) of acetic anhydride in 50 ml of acetic acid was refluxed for 3 hours in a nitrogen atmosphere. The mixture was evaporated and the oily residue was made slightly alkaline (pH=9.2) with a 10% sodium hydroxide solution. The precipitate was filtered off, and triturated with a mixture of water (1000 ml) and heptane (500 ml). The precipitate was filtered off, dried and resuspended in 400 ml of heptane. The resulting precipitate was filtered off and dried to yield 65.7 g (80%) of 5-acetylamino-2-n-propylpyridine. M.p. 122-24° C. 1H-NMR (CDCl3, 200 MHz) δ: 0.95 (t, 3H), 1.72 (sext, 2H), 2.20 (s, 3H), 2.73 (t, 2H), 7.10 (d, 1H), 7.70 (br s, 1H), 8.09 (dd, 1H), 8.43 (d, 1H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:6]=1[C:15](=[O:19])[CH:16]([CH3:18])[CH3:17].Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[C:15](=[O:19])[CH:16]([CH3:17])[CH3:18]
Reactant: COCOc1cccc(OCOC)c1C(=O)C(C)C
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)c1c(O)cccc1O
Yield: 86.3 %

Procedure:
1-(2,6-bis{[(methyloxy)methyl]oxy}phenyl)-2-methyl-1-propanone (Intermediate 36, 1.58 g, 5.89 mmol) was dissolved in methanol (40.0 ml) and an aqueous solution of HCl (23.6 mL of a 2M aqueous solution, 47.1 mmol) was added. The reaction mixture was refluxed for 1 hour. After quenching with water, the reaction mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound (916 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26]C(C)C)=[CH:17][N:18]=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[OH:26])=[CH:17][N:18]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2cc(Cl)ccc2OC(C)C)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
Add aluminum(III) chloride (6.67 g, 50 mmol) portionwise to a solution of 7-[5-(5-chloro-2-isopropoxyphenyl)thiazol-2-yl]heptanoic acid methyl ester (9.90 g, 25 mmol) in methylene chloride (300 mL) at 0° C. under nitrogen. Slowly warm the mixture to room temperature and stir for an additional 30 minutes. Cool the mixture to 0° C., treat with saturated aqueous sodium sulfate Na2SO4 (150 ml), and stir for 1 hour. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate (300 mL), wash with water (100 mL) and brine (100 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:9 to 1:1), to afford 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid methyl ester (5.67 g, 64%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.C(OC([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)=O)(C)(C)C.CC(O)=O>CC(N(C)C)=O>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:36][C:32]1[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Br)c3n2)nc1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(Br)cccc23)n[nH]1
Temperature: 100 °C
Yield: 21.8 %

Procedure:
To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline (0.19 g, 0.49 mmol) in DMA (1.0 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.30 g, 1.53 mmol) and HOAc (0.065 mL, 1.1 mmol) and the mixture was heated to 100° C. for 5 h. The mixture was allowed to cool to rt and purified by reverse phase HPLC (ammonium acetate modifier). Fraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL) and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (48 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.22 (br s, 1H), 10.87 (br s, 1H), 8.57-8.81 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.02 (d, J=5.3 Hz, 2H), 7.54 (t, J=7.9 Hz, 1H), 5.95 (s, 1H), 2.17 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a solution of 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 3 mL 50% aqueous tetrahydrofuran were added 0.43 mL (0.86 mMol) 2N sodium hydroxide followed by 0.065 mL (0.56 mMol) benzoyl chloride and the resulting mixture was stirred at room temperature. After about 4 hours the reaction mixture was partitioned between dichloromethane and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane (2-10% methanol) containing 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.095 gm (66%) of the title compound. A portion was recrystallized from ethanol/water to provide an analytical sample.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>Cl.CN1C(=O)CCC1.O>[ClH:1].[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.072 g, 0.27 mmol), 4-fluoroaniline (0.052 mL, 0.54 mmol) and cone. HCl (1 drop) in NMP (2 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 3 h. After this time, the reaction mixture was cooled, diluted with water (25 mL) then treated with saturated sodium bicarbonate until pH˜8 and extracted with ethyl acetate. The combined extract was washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as the eluent to afford the free base of the title compound (0.064 g, 70%) as an oil. MW=338.81. 1H NMR (DMSO-d6, 500 MHz) δ 8.14 (s, 1H), 7.93-7.90 (m, 1H), 7.76 (dt, J=7.0, 2.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.31-7.26 (m, 2H), 7.24-7.18 (m, 2H), 7.13 (s, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.09 (quin, J=7.5 Hz, 2H). Treatment with 1.25M HCl in methanol (0.15 mL, 0.19 mmol, 1.0 eq.) afforded the title compound (0.064 g, 91%) as a white solid. MW=375.27. M.p. 103-106° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.99 (br s, 1H), 9.05 (br s, 1H), 7.92-7.89 (m, 1H), 7.75-7.70 (m, 1H), 7.57-7.49 (m, 2H), (m, 2H), 7.31-7.25 (m, 2H), 7.04 (s, 1H), 3.04 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H); ESI MS m/z 339 [m+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](Br)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: COc1cc(CC#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCCCOc1ccc(CC#N)cc1OC
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A mixture of 15 grams 4-hydroxy-3-methoxyphenylacetonitrile (91.91 mmol), 26.40 ml (33.59 grams) n-butyl bromide (245 mmol) and 21.17 grams potassium carbonate (153.2 mmol) in 150 ml acetone was heated to reflux under nitrogen for 18 hours. After cooling to room temperature, the mixture was diluted with diethyl ether and the inorganic salts were removed by filtration and were washed with diethyl ether. The filtrate and wash solutions were evaporated in vacuo to provide 21.11 grams of Compound 10c as a straw-colored viscous oil (99.9% yield) which was dried in vacuo at 50° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[C].[Pd].O1CCCC1>[C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Yield: 90.3 %

Procedure:
A 200 mg quantity of 10% palladium carbon was added to a tetrahydrofuran (50 ml) solution of 1.75 g of methyl 4-(3-phenyl-2-oxooxazolidin-5-yl)methoxycinnamate (compound 185) obtained in Example 29. The mixture was stirred at room temperature for 2.5 hours in a stream of hydrogen at 3 atmospheric pressure. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and washed with methanol to give 1.59 g of the title compound (compound 189) in a yield of 88%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:7])[CH3:2].S(Cl)([Cl:19])(=O)=O>CCOCC>[Cl:19][CH:5]([C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1Cl
Reaction time: 4 h
Yield: 93.6 %

Procedure:
To a stirred solution of 3-(2-chloro-phenyl)-3-oxo-propionicacidethylester (5.000 mL, 26.600 mmol) in ether (75.00 mL) was added dropwise sulfuryl chloride (2.800 mL, 34.600 mmol) and the resulting solution was stirred for 4 h. The reaction mixture was diluted with ether (50.0 mL) and quenched by the slow addition of a saturated aqueous solution of sodium bicarbonate (50.0 mL) and the mixture was vigorously stirred for 30 min. The organic phase was separated and dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide 6.500 g of crude product as a clear colorless oil (100%). The crude residue was used without further purification. LC/MS (AA) ES+ 261, 263. 1H NMR (400 MHz, d, CDCl3) δ: 12.47 (s, 1H), 7.49-7.32 (m, 4H), 4.39 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).