Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:4]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][N+:21]=1[O-:33]>CN(C)C=O>[N:27]1([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([C:5]5[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=5)[CH:10]=4)[NH:14][C:13]=3[OH:18])=[N+:21]([O-:33])[CH:22]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Reactant: O=C1Cc2cc(-c3cccnc3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(-c3cccnc3)cc12
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 82.8 %

Procedure:
To a suspension of sodium hydride (0.05 g, 1.2 mmol, 60% dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide (3 mL) was added a solution of 5-pyridin-3-yl-1,3-dihydro-2H-indol-2-one (0.19 g, 0.90 mmol) in N,N-dimethylformamide (4 mL). The mixture was stirred for 20 min under nitrogen atmosphere. 2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (0.14 g, 0.60 mmol), dissolved in N,N-dimethylformamide (3 mL) was added dropwise and the mixture was stirred at room temperature for 2 h and then heated at 130° C. for 1.5 h. The solvent was evaporated in vacuo and the residue was partitioned between 2 M HCl and ethyl acetate and the phases were separated. The aqueous layer was alkalized by addition of NaHCO3 (s) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo affording 200 mg of the title compound as a yellow solid: MS (ES) m/z 403 (M++1).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:25]([C:29]1[N:30]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:31]([CH:35]=[O:36])=[C:32]([Cl:34])[N:33]=1)[CH2:26][CH2:27][CH3:28].C1CCN2C(=NCCC2)CC1>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([NH:47][S:44]([C:41]1[CH:42]=[CH:43][C:38]([CH2:37][N:30]2[C:31]([CH:35]=[O:36])=[C:32]([Cl:34])[N:33]=[C:29]2[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:39][CH:40]=1)(=[O:46])=[O:45])=[O:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
N-Boc-glycine (2.8 g, 16 mmol, 1.0 eq) was dissolved into 50 mL THF. CDI (2.6 g, 16 mmol, 1.0 eq) was added, and the mixture heated to 80° C. for 2 hours. The solution was cooled to room temperature and added to a solution of intermediate (2c) (5.7 g, 16 mmol, 1.0 eq) in 100 mL THF followed by DBU (2.4 mL, 16 mmol, 1.0 eq). The mixture was stirred at room temperature overnight. The mixture was then concentrated, redissolved into 100 mL EtOAc, washed with saturated bicarbonate, saturated aqueous NaCl, dried over MgSO4, and evaporated. The residue was chromatographed (10% MeOH:EtOAc with 0.7% NH3) to yield intermediate (2d) (5.6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[C:10]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: COc1ccc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 4-methoxyphenylboronic acid. Yield 0.610 g
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:21])[CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20]>N1C=CC=CC=1>[S:7]([O:21][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CCC#CC=CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCC#CC=CCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a mixture of p-toluenesulfonyl chloride (22.4 g., 0.12 moles) and50 ml. of anhydrous pyridine is added 14 g. of non-4-en-6-yn-1-ol (0.107 moles) with ice bath cooling. The mixture is stirred for 1 hour and then is stored at 0° overnight. Ice is added to the mixture which is extracted with several portions of 50:50 ether/hexane. The combined organic phase is washed with 5% HCl, water, saturated sodium bicarbonate and dried over sodium sulfate. Removal of solvent at reduced pressure and subsequent solvent removal at 0.15 mm. for 1 hour gives 1-tosyloxy-non-4-en-6-yne (28 g.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of (3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (2.50 g, 6.61 mmol) in CH3CN (55 mL) was added 2,2,2-trichloroethyl chloroformate (1.34 mL, 9.91 mmol) and stirring was continued for 4 hours at RT. Volatiles were removed under vacuo, and the residue was dissolved in AcOH (25 mL). Then Zn dust (1.20 g) was added portion wise. After three hours at RT the reaction mixture was filtered on celite, the solvent removed under vacuo followed by an extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 1.85 g (97%) of the title compound as a light yellow oil. ES-MS m/e: 288.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:7]1[C:2]([F:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Cl)cnc21
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
4-Fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 10.258 mmol) was placed in THF (15 mL) at −78° C. s-BuLi (16.12 mL, 22.57 mmol) was then added dropwise and stirred for 30 minutes. Hexachloroethane (6.07 g, 25.6 mmol) in THF (10 mL) was then added rapidly, and the reaction was stirred for an additional 30 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted into hexanes. The combined organic fractions were dried, filtered and concentrated to give the crude product that was purified by column chromatography (hexanes) to give 5-chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.1 g, 62% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][S:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([NH:26][CH2:25][CH2:24][CH2:23][S:22][CH3:21])[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CSCCCN
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Product: CSCCCNc1cc(-c2cccc3[nH]ncc23)nc2c1cnn2C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (100 mg) and 3-(methylthio)propylamine (3 equiv.) were heated in microwave at 170° C. for one hour following General Procedure B. Volatiles were removed in vacuo; the residue was purified by prep HPLC to give [6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-(3-methylsulfanyl-propyl)-amine (94 mg) as a white solid. 3-Chloroperoxybenzoic acid (MCPBA, 94 mg, 2.2 equiv.) in 2 ml dry DCM was added at 0° C. The reaction mixture was allowed slowly to warm up to room temperature over 3 hours and extracted with DCM, washed with saturated aqueous sodium hydrogen carbonate and purified by flash chromatography (methanol/DCM) to give 116 (27 mg) as a white solid. NMR (CDCl3): 2.39 (2H, m), 3.00 (3H, s), 3.25 (2H, t), 3.74 (2H, m), 4.20 (3H, s), 5.20 (1H, br t), 6.77 (1H, s), 7.50-7.54 (1H, m), 7.59 (1H, d), 7.70 (1H, d), 7.97 (1G=H, s), 8.82 (1H, s), 10.20 (1H, br). MS: MH+ 385.19 (100%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:28])[CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccccc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-phenylindole-3-carboxylic acid ethyl ester (140 mg, 0.38 mmol, see step (b) Example 3) and 3-chlorophenylboronic acid (119 mg, 0.76 mmol). Yield 53 mg (29%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:23]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH2:35][CH3:36])(=O)=O.Cl.C([O:40][C:41](=[O:44])[CH2:42][NH2:43])C>>[CH:30]1([C:24]2[CH:23]=[C:22]([C:20]3[O:19][N:18]=[C:17]([C:13]4[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:43][CH2:42][C:41]([OH:40])=[O:44])=[C:11]([CH2:35][CH3:36])[CH:12]=4)[N:21]=3)[CH:27]=[C:26]([O:28][CH3:29])[N:25]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCOS(C)(=O)=O
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCNCC(=O)O
Yield: 41 %

Procedure:
The title compound (59 mg) is prepared as a pale yellow solid in analogy to the procedures given in Example 1 starting from 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propyl methanesulfonate (150 mg, 0.291 mmol) and glycine ethyl ester hydrochloride (203 mg, 1.46 mmol); LC-MS: tR=0.96 min, [M+H]+=495.25; 1H NMR (CD3OD): δ 7.88 (s, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 3.98-4.03 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.38-3.44 (m, 2H), 3.24-3.31 (m, 1H), 2.78 (q, J=7.6 Hz, 2H), 2.41 (s, 3H), 2.23-2.32 (m, 2H), 2.06-2.17 (m, 2H), 1.85-1.97 (m, 4H), 1.72-1.82 (m, 2H), 1.32 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]3([CH2:76][CH2:75][CH2:74][CH2:73]3)[O:71][B:70]([OH:77])[C:69]=2[CH:78]=1>CN(C=O)C>[OH:77][B:70]1[C:69]2[CH:78]=[C:65]([CH2:64][NH:63][C:19](=[O:21])[C:18]3[CH:22]=[CH:23][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:25]([F:26])([F:28])[F:27])[O:14][N:13]=4)=[CH:16][C:17]=3[CH3:24])[CH:66]=[CH:67][C:68]=2[C:72]2([CH2:73][CH2:74][CH2:75][CH2:76]2)[O:71]1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCc1ccc2c(c1)B(O)OC21CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC21CCCC1
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
A solution of 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (0.3 g, 0.67 mmol) and DIPEA (346 mg, 2.68 mmol) in DMF (10 mL) was stirred at rt for 5 min and then HATU (510 mg, 1.34 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclo-pentan]-1-ol hydrochloride (202 mg, 0.80 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified on column chromatography and prep-HPLC to provide the product (150 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.89 (t, 1H), 7.82 (s, 2H), 7.59 (t, 3H), 7.44 (m, 2H), 7.36 (d, 1H), 4.45 (d, 2H), 4.36 (d, 1H), 4.28 (d, 1H), 2.41 (s, 3H), 1.99 (m, 8H) ppm; HPLC purity: 98.37% at 220 nm and 98.66% at 254 nm; MS: m/z=652.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: NC1CCCC1
Product: O=C(Nc1nc2cccc(NC3CCCC3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30, but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 44 mg; 0.16 mmol; 1.0 eq.) and cyclopentylamine (1.0 mL) as a white powder (23 mg, 44%). HPLC, Rt: 3.06 min. (purity 99.5%). LC/MS, M+(ESI): 322.1, M−(ESI): 320.1.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[N:57][O:58][CH3:59])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:74]>CO.O>[ClH:74].[CH3:59][O:58][N:57]=[C:56]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[O:49][C:48]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[C:47]1[C:44]1[CH:43]=[CH:42][C:41]([C:37]2([NH2:36])[CH2:40][CH2:39][CH2:38]2)=[CH:46][CH:45]=1
Reactant: CON=c1c(-c2ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc2)c(-c2ccccc2)oc2ccccc12
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CON=c1c(-c2ccc(C3(N)CCC3)cc2)c(-c2ccccc2)oc2ccccc12
Yield: 69 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(4-methoxyimino-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (2 mL), water (6 mL) and 1 M HCl (0.1 mL) and chromatographed on a 5 g C18 cartridge {35 to 80% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (13.3 mg, 69%). 1H NMR (400 MHz, CD3OD): δ 8.89 (dd, J=8.4 and 1.4 Hz, 1H), 7.54-7.50 (m, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.33-7.16 (m, 9H), 3.77 (s, 3H), 2.80-2.73 (m, 2H), 2.60-2.52 (m, 2H), 2.28-2.17 (m, 1H), 2.01-1.90 (m, 1H). LCMS (Method E): RT=4.10 min, [M+H]+=397.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:35]([C:27]2[C:28]3[O:33][CH2:32][O:31][CH2:30][C:29]=3[CH:34]=[C:25]([F:24])[CH:26]=2)=[O:36])=[O:8])[N:6]=1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(F)cc3c2OCOC3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=513.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](N)=[O:8].CN(C)C=[O:13]>S(Cl)(Cl)=O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:8])=[O:13]
Reactant: NC(=O)c1cnccn1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(O)c1cnccn1
Reaction time: 0.08 h
Yield: 111.6 %

Procedure:
Thionyl chloride (10 mL) is added to a 25 mL round bottom flask in an ice bath. To the flask is added 800 mg (6.5 mmole) of 2-Pyrazinecarboxylic acid 74, and the mixture stirred for 5 minutes. Dimethyl formamide (1.02 g mg, 14 mmole) is added in a single portion, and the orange/red solution stirred for 90 minutes. The solvents are removed under reduced pressure to give 80 (0.900 g).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:33])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH3:25])[C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[N:19]([C:30](=[O:32])[CH3:31])[CH2:18]2)[CH3:14])=CC=1)([O-])=O.[F:35][C:36]1[C:43]([F:44])=[CH:42][C:41]([F:45])=[CH:40][C:37]=1[CH2:38][NH2:39]>O1CCOCC1>[C:30]([N:19]1[CH2:18][C@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:39][CH2:38][C:37]2[CH:40]=[C:41]([F:45])[CH:42]=[C:43]([F:44])[C:36]=2[F:35])[CH3:14])=[O:33])[C:23](=[O:24])[N:22]([CH3:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]1=2)(=[O:32])[CH3:31]
Reactant: NCc1cc(F)cc(F)c1F
Reactant: CC(=O)N1C[C@H](NC(=O)[C@H](C)OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N(C)c2ccccc21
Solvent: C1COCCO1
Product: CC(=O)N1C[C@H](NC(=O)[C@H](C)OC(=O)NCc2cc(F)cc(F)c2F)C(=O)N(C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 57 d), the aminolysis of the carbonic acid (S)-1-((S)-5-acetyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl)-ethyl ester 4-nitro-phenyl ester by 2,3,5-trifluoro-benzylamine in dioxane yielded the title compound as a light yellow solid; MS: m/e=510 (M+NH4)+.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:10][CH2:11][C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[SH:10][CH2:11][C:12]([O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: OC1CCCCCCC1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CS)OC1CCCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 32 grams of cyclooctanol; 9.2 grams of mercaptoacetic acid and 0.5 grams paratoluene sulfonic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]#[N:15])[CH2:10][CH2:9][CH2:8]2)(=O)[CH3:2].[OH:16]O.[OH-].[Na+].O>C(O)C>[CH3:2][C:1]1[NH:15][C:14](=[O:16])[C:13]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][C:11]=3[CH:12]=2)[N:4]=1
Reactant: OO
Reactant: CC(=O)Nc1cc2c(cc1C#N)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)CCC3
Temperature: 50 °C

Procedure:
A mixture of 5-acetamido-6-cyanoindan (104 g), hydrogen peroxide (30% solution in water, 400 ml), sodium hydroxide (35 g), water (200 ml) and ethanol (1 L) was stirred and heated to 50° C. for 1 hour. The mixture was cooled to ambient temperature and evaporated. The residue was dissolved in water (2 L) and the solution was acidified to pH 5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 2-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (100 g), m.p. 284° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:5]=[CH:6][C:7]([NH:9][C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([O-:14])=[O:13])=[O:8].[NH2+]1CCCCC1.Cl>O.CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:5]=[CH:6][C:7]([NH:9][C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])=[O:8]
Reactant: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)[O-])cc1O
Agent: C1CC[NH2+]CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1O
Yield: 97 %

Procedure:
A 10 g quantity of piperidinium N-(3-hydroxy-4-methoxycinnamoyl)anthranilate is dissolved in a mixture of 80 ml of water and 80 ml of methyl alcohol with heating, and the resultant solution is added dropwise to 85 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 80 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield N-(3-hydroxy-4-methoxycinnamoyl)anthranilic acid (97.0% yield), m.p. 219°-222° C. The compound structure is confirmed by elemental analysis, and by IR and NMR spectroscopy.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][NH:19]C(=O)OC(C)(C)C)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:19][CH2:18][C:16]1[N:17]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
tert-Butyl (6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylcarbamate (0.25 g, 0.67 mmol) was dissolved in trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated and the residue was recrystallized from methanol-diisopropyl ether to give the titled compound (0.22 g, 85%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:15]Br>CCOCC>[Br:15][CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:14]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2cc([N+](=O)[O-])ccc2CCC1Br

Procedure:
To a suspension of 9.56 g (0.05 mol) of 7-nitro-1-tetralone in 250 mL of ether was added bromine dropwise. The progress of the reaction was followed by thin layer chromatography (fl. silica gel/CH2Cl2). When all of the starting material had been consumed, the mixture was concentrated and cyclohexane was added. The white solid was removed by filtration to afford 2.25 g of 2-bromo-7-nitrotetralone, mp 94°-96° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][C:23]([F:26])([F:25])[F:24])[CH:16]=1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[CH:16][C:17]=1[O:22][C:23]([F:24])([F:26])[F:25]
Reactant: O=C(O)CCc1cccc(O)c1
Reactant: FC(F)(F)Oc1cc(CBr)ccc1Cl
Product: O=C(O)CCc1cccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)c1

Procedure:
Compound 37.3 was synthesized using the alkylation and hydrolysis procedure of Example 13 above using compounds 37.1 and 37.2. 3-(3-Hydroxyphenyl)propanoic acid is available from Alfa Aesar Avocado, and Lancaster). 4-(Bromomethyl)-1-chloro-2-(trifluoromethoxy)benzene is available from Alfa Aesar, Lancaster, and Avocado. MS ESI (neg.) m/e: 373 (M−H).