Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(CC)CC.[CH3:23][C:24]1[C:33]2[CH2:32][CH2:31][C:30](=[O:34])[NH:29][C:28]=2[N:27]=[C:26]([O:35][CH2:36][CH2:37][CH2:38][CH:39]=O)[CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:26]2[N:27]=[C:28]3[C:33]([CH2:32][CH2:31][C:30](=[O:34])[NH:29]3)=[C:24]([CH3:23])[CH:25]=2)[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: Cc1cc(OCCCC=O)nc2c1CCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)nc2c1CCC(=O)N2
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To a suspension of 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.93 g, 3.48 mmol) in dichloroethane (10 mL) was added Et3N (0.96 mL, 6.92 mmol). The mixture was stirred for 15 min and a suspension of 4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.86 g, 3.46 mmol) in dichloroethane (5 mL) was added. After 20 min at RT, NaBH(OAc)3 (1.03 g, 4.85 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction mixture was poured into CH2Cl2 and washed with H2O, 1N citric acid, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to an oil. Et2O was added and the organics were decanted from an insoluble gum. The filtrate yielded a crystalline solid, which was collected by filtration and dried. Purification by liquid chromatography (gradient elution, 100% CHCl3 to 2% MeOH/CHCl3, Biotage 40m column) provided the title compound as a white solid (1.12 g, 2.44 mmol, 70%). MS: APCI: M+1: 463.1 (Exact Mass: 462.16).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[K+].O>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(c1)C(C)(C)CN2C(C)=O
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2(C)C
Temperature: 0 °C
Yield: 86.5 %

Procedure:
A solution of 1-acetyl-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indole (2.44 g, 11.13 mmol, see PCT Int. Appl. (2001), WO 2001023374 A1 20010405) in trifluoroacetic acid (50 mL) was stirred at 0° C. and potassium nitrate (1.181 g, 11.68 mmol) was added in one portion. The reaction was maintained at 0° C. for 3 hours and poured into water. The solids were collected via filtration to afford 1-acetyl-3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.545 g, 87% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1 H), 7.34 (s, 1 H), 3.91 (s, 3 H), 2.15 (s, 2 H), 1.36 (s, 6 H). Note: proton resonance corresponding to acetyl was extremely broad and/or not evident for a variety of lots.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:5]=2[O:4][CH2:3][CH2:2]1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C)[N:22]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]([NH:14][S:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:12])=[O:13])=[O:30])[N:22]=1
Reactant: NS(=O)(=O)c1cccc2c1OCCO2
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OCCO3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.0 g 1,4-benzodioxan-5-sulfonamide, prepared in Example 15, in 50 ml methylene chloride at ambient temperature under nitrogen was added 2.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at ambient temperature, 1.0 g of methyl [4-methoxy-6-methylpyrimidin-2-yl]carbamate, prepared according to the procedure of Example 3, was added and the reaction mixture was heated at reflux for 72 hours. The reaction mixture was cooled to ambient temperature and 75 ml water, 10 ml glacial acetic acid and 10 drops hydrochloric acid were sequentially added. The organic phase was separated, dried, and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from n-butyl chloride/ether gave a solid, m.p. 203°-205° C. IR(mull) 1700 (c=o) cm-1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH:15]=[O:16].[CH3:24][C:25](=[O:28])[CH:26]=[CH2:27]>COCCOC.C(OCC)(=O)C.O>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])([CH2:27][CH2:26][C:25](=[O:28])[CH3:24])[CH:15]=[O:16]
Reactant: C=CC(C)=O
Reactant: O=CC(c1ccccc1F)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(=O)CCC(C=O)(c1ccccc1F)c1ccccc1F
Temperature: -50 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (26.9 g) is added to a solution of bis-(2-fluorophenyl)acetaldehyde (30.8 g) in 1,2-dimethoxyethane (135 cc) and, after cooling to -50° C., butenone (19.9 cc) is then added dropwise. The reaction mixture is stirred for 12 h at -50° C. and then for 6 hours at 25° C. and diluted with ethyl acetate (250 cc) and water (200 cc). The organic phase is washed with water (3×200 cc) and then with saturated sodium chloride solution (200 cc), dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 5.5 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10). 2,2-bis-(2-Fluorophenyl)-5-oxohexanal (9 g) is obtained in the form of a yellow oil. A solution of this compound (6.65 g) in toluene (100 cc) containing paratoluenesulphonic acid (1.5 g) is refluxed for 3 hours, washed with water (2×100 cc) and then with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 4 cm, height 30 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10) and collecting 15 cc fractions. Fractions 21 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 4,4-bis-(2-fluorophenyl)-cyclohexenone (2.83 g) in the form of yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH2:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:24]>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCN1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CCN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4CC)CC1
Yield: 70.4 %

Procedure:
1-Ethyl-8-(4-ethyl-1-piperazinyl)-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.3 g of 1-ethylpiperazine in 16 cm3 of pyridine. 1.4 g of 1-ethyl-8-(4-ethyl-1-piperazinyl)-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 287°-288° C., solvated by 1.6% of water.
Reaction SMILES: O(Cl)Cl.[P+5].[NH2:5][C:6]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1.[C:37]([O:41][C:42]([NH:44][C@H:45]([C:61](O)=[O:62])[CH:46]([C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1)[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>N1C=CC=CC=1>[C:37]([O:41][C:42]([NH:44][C@H:45]([C:61]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:11]1)=[O:62])[CH:46]([C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1)[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)=[O:43])([CH3:39])([CH3:40])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(N)cccc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: ClOCl
Agent: [P+5]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Phosphorus (V) oxychloride (118 μl, 1.262 mmol) was added to a solution of tert-butyl (2S,5S)-2-[(2-amino-6-fluorophenoxy)methyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (540 mg, 1.147 mmol) and N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (433 mg, 1.147 mmol) in pyridine (5.74 mL) at −15° C. The reaction was stirred for 30 minutes then warmed to 0° C. and stirred for another 1.5 hours. LC/MS at this time only shows pyridine and desired product. The reaction was quenched with a saturated aqueous solution of KH2PO4 and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (977 mg, 1.106 mmol, 96% yield) as an off-white foam, MS (ESI): m/z=730.51 (M+H-boc). 94% pure by LC/MS. The material was taken on crude to the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:19][CH3:20])[C:6]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8](=[O:15])[C:7]=2[C:16]=1[O:17]C)[CH3:2].Br.C(=O)(O)[O-].[Na+].Cl>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:19][CH3:20])[C:6]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8](=[O:15])[C:7]=2[C:16]=1[OH:17])[CH3:2]
Reactant: CCc1cc(CC)c2oc(C(=O)O)cc(=O)c2c1OC
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Product: CCc1cc(CC)c2oc(C(=O)O)cc(=O)c2c1O

Procedure:
A mixture of 5 parts of 6,8-diethyl-5-methoxy-4-oxo-4H-1-benzopyran-2-carboxylic acid and 130 parts by volume of 48% aqueous hydrobromic acid was refluxed for seven hours. The reaction mixture was cooled and excess sodium bicarbonate solution was added. The solution was acidified with concentrated hydrochloric acid and then extracted with chloroform. Evaporation of the chloroform gave a residue which on trituration with light petroleum gave 2.3 parts of 6,8-diethyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid, m.p. 218°-220° C (after crystallization from ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:15]=1)=O.F[C:30]1[C:35](C(F)(F)F)=[CH:34][CH:33]=[CH:32][C:31]=1[C:40]([C:42]1C=CC=C(OC2C=CC(OC)=CC=2)[CH:43]=1)=O>>[CH2:40]([C:42]1[CH:43]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH:15]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1
Reactant: COc1ccc(Oc2cccc(C(=O)c3cccc(C(F)(F)F)c3N)c2)cc1
Reactant: COc1ccc(Oc2cccc(C(=O)c3cccc(C(F)(F)F)c3F)c2)cc1
Product: COc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
[2-amino-3-(trifluoromethyl)phenyl][3-(4-methoxyphenoxy)phenyl]methanone: The title compound was prepared from (2-fluoro-3-trifluoromethylphenyl)-[3-(4-methoxy-phenoxy)-phenyl]methanone (0.64 g, 0.0015 mole) following the procedure of Example 457, Step 3: MS (ESI) m/z 388;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:3]=1>[Ni].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[C:4]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:3]=1
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Agent: [Ni]
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1CCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 9.6 g (23 mmole) of 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropyne and 1 teaspoonful of Raney nickel in 70 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure. When 1.05 L of hydrogen was absorbed the catalyst was separated by filtration and the filtrate was concentrated at reduced pressure to dryness. The residue crystallized from a mixture of ether and petroleum ether to give the product as a tan solid, mp 98°-99° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:29]1([NH:35][C:36]([C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:42]([C:41]5[CH:40]=[CH:39][C:38]([C:36](=[O:37])[NH:35][C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)=[CH:45][CH:44]=5)=[N:1][C:4]=4[CH:5]=3)=[O:28])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)cc2)CC1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Product: CN1CCN(c2ccc(C(=O)Nc3ccc4[nH]c(-c5ccc(C(=O)Nc6ccccc6)cc5)nc4c3)cc2)CC1

Procedure:
Compound 216 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(1-methyl-4-piperazinyl)benzamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C32H30N6O2: 531.25; found: 531.05.
Reaction SMILES: CC1C=C(C(=O)C[C@H](C2C=CC(C3C=CC(C(NCC(O)=O)=O)=CC=3)=CC=2)C2C=CC=CC=2C)C=CN=1.Cl.NO.C([O-])(O)=O.[Na+].[OH:46][N:47]=[C:48]([C:77]1[CH:82]=[CH:81][N:80]=[C:79]([CH3:83])[CH:78]=1)[CH2:49][C@H:50]([C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][C:67]([C:70]([NH:72][CH2:73][C:74]([OH:76])=[O:75])=[O:71])=[CH:66][CH:65]=2)=[CH:60][CH:59]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57]>>[OH:46]/[N:47]=[C:48](/[C:77]1[CH:82]=[CH:81][N:80]=[C:79]([CH3:83])[CH:78]=1)\[CH2:49][C@H:50]([C:58]1[CH:59]=[CH:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([C:70]([NH:72][CH2:73][C:74]([OH:76])=[O:75])=[O:71])=[CH:66][CH:65]=2)=[CH:62][CH:63]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57]
Reactant: Cc1cc(C(C[C@H](c2ccc(-c3ccc(C(=O)NCC(=O)O)cc3)cc2)c2ccccc2C)=NO)ccn1
Agent: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)NCC(=O)O)cc3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: NO
Product: Cc1cc(/C(C[C@H](c2ccc(-c3ccc(C(=O)NCC(=O)O)cc3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 7, from ({4′-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carbonyl}-amino)-acetic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared ({4′-[(R)-3-[hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-biphenyl-4-carbonyl}-amino)-acetic acid as a mixture of isomers which was separated by chiral HPLC (Reprosil-Chiral-NR, 70% n-heptane, 30% ethanol+0.5% formic acid) to give the title compound as a white solid, MS (ESI+): m/z=508.3 ([M+H]+).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([O:5][C:6](=[O:37])[NH:7][C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH:22]=3)[CH:16]=2)[N:11]([C:33](=[O:35])[CH3:34])[C@@H:10]([CH3:36])[CH2:9]1)[CH3:4].CCOCC>O1CCOCC1>[ClH:1].[C:33]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][NH2:25])[CH:22]=3)=[CH:14][CH:13]=2)[C@H:8]([NH:7][C:6](=[O:37])[O:5][CH:3]([CH3:2])[CH3:4])[CH2:9][C@@H:10]1[CH3:36])(=[O:35])[CH3:34]
Reactant: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)N1c2ccc(-c3cn(CCN)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
HCl (4M in 1,4-dioxane, 2 mL, 8 mmol) was added to a solution of 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-1,2,3-triazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see intermediate 77) (108 mg, 0.22 mmol) in 1,4-dioxane (0.5 mL). The mixture was stirred at room temperature for 16 h. Et2O (5 mL) was added and the mixture stirred for 1 h. The solid formed was filtered off, washed with Et2O and dried under house vacuum to give 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-aminoethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (75 mg, 0.172 mmol, 80%) as a colourless solid. LCMS (method G): Retention time 0.55 min, [M+H]+=401.1
Reaction SMILES: [ClH:1].N[C@@H](C)[C@@H](C1C=CC(SC)=CC=1)O.[O:15]=[C:16]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(O)C>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[NH2:19][C@@H:17]([CH3:18])[C@@H:16]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)[OH:15]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1cnc2ccccc2c1
Agent: CC(C)[O-]
Agent: CSc1ccc([C@@H](O)[C@H](C)N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C[C@H](N)[C@H](O)c1cnc2ccccc2c1

Procedure:
Following the procedure described for preparation of 29b. Starting from (S)-tert-butyl 1-oxo-1-(quinolin-3-yl)propan-2-ylcarbamate (42c, 1.6 g, 5.33 mmol), Aluminium isopropoxide (0.68 g, 3.33 mmol) and 2-propanol (4.5 mL, 59.16 mmol) in toluene (7 mL) stirred at +50° C. in sealed reaction tube flushed with argon for 16 hours. Work up and deprotection of the intermediate BOC-protected amine afforded the subtitle compound as a colourless solid. Yield 1.29 g (88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]2[CH:19]3[CH:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4Cl)[O:13]2)[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH3:41][NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]2[CH:19]3[CH:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4[N:42]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:41])[O:13]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCC2OC(n3cnc4c(Cl)ncnc43)C3OC(C)(C)OC23)no1
Reactant: CNCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC2OC(n3cnc4c(N(C)Cc5ccccc5)ncnc43)C3OC(C)(C)OC23)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (0.106 g, 0.23 mmol) in tetrahydrofuran (1.2 mL) was added polymer-bound diisopropylethylamine (PS-DIEA; Argonaut Tech., 3.83 mmol/g, 0.190 g, 3 eq), followed by addition of 0.040 mL of N-methyl-N-benzylamine (1.2 eq). The resulting mixture was stirred at room temperature overnight. The PS-DIEA resin was washed three times with dichloromethane and the solution obtained from the washes was concentrated to yield 3-{6-[6-(N-Benzyl-N-methyl-amino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-isoxazole-5-carboxylic acid methyl ester as yellow oil. This material (0.23 mmol) was dissolved in 1,4-dioxane (1.2 mL) and 0.250 mL of an aqueous 2M lithium hydroxide solution added. The mixture was stirred at room temperature for 4 h. The crude product, isolated after acid workup, was used without further purification in the following step. MW calculated for C25H26N6O7 (MH+): 523, found 523 by LCMS.
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)(=[O:3])[CH3:2].S(Cl)([Cl:29])(=O)=O>C(Cl)(Cl)Cl.Cl.C(OCC)(=O)C.CCOCC>[Cl:29][CH2:2][C:1]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)CCl)c3c2)c1=O
Temperature: 25 °C

Procedure:
To a solution of 3-(3-acetyl-1,2-benzisothiazol-5-yl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.570 g, 0.00154 mol) in chloroform is added sulfuryl chloride (0.350 ml, 0.00433 mol). The resultant mixture is stirred one hour at reflux. Concentrated hydrochloric acid (one drop) is added followed by sulfuryl chloride (1.05 ml, 0.0130 mol) and the resultant mixture is stirred three days at reflux. The mixture is cooled to room temperature, diluted with ethyl acetate and ether, washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to a solid. The resultant solid is chromatographed on silica gel with hexanes:ethyl acetate to afford a white solid. The solid is chromatographed on silica gel with chloroform to afford a white solid, which is recrystallized from ethyl acetate and hexanes to give the title compound as a white crystalline solid (mp 215-215° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[C:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH2:58])[CH3:57])=[CH:51][CH:50]=2)=[CH:43][CH:42]=1)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[C:48][C:49]2[CH:50]=[CH:51][C:52]([CH2:55][CH:56]([NH:58][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[CH3:57])=[CH:53][CH:54]=2)=[CH:43][CH:42]=1)[CH3:39]
Reactant: CCOc1ccc(C#Cc2ccc(CC(C)N)cc2)cc1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)NC(C)Cc1ccc(C#Cc2ccc(OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.41 mg (0.10 mmol) butanoic acid are dissolved in 300 μL DMF together with 32.1 mg (0.10 mmol) TBTU and 50.0 μL (0.30 mmol) DIPEA and the mixture is stirred at r.t. for 5 min. 27.9 mg (0.10 mmol) 1-(4-((4-ethoxyphenyl)ethynyl)phenyl)propan-2-amine (I64) are added and the reaction mixture is stirred at 40° C. over night. The mixture is filtered through a plug of alox, eluted with DMF/MeOH (9/1) and the solvent is removed in vacuo. The residue is purified by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1>C(O)C.[Pd]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN1CCCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A solution of compound 4 (0.8 g, 3.208 mmol) in dry ethanol (20 mL) was treated with Pd—C (˜0.08 g) and purged with hydrogen gas. The reaction was stirred at room temperature under hydrogen atm. for 3 h. The reaction was filtered through celite bed and washed with methanol (3×20 mL). The combined organic layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 5 (0.6 g, 86%).