Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH2:12][OH:13])=[CH:5]2>C(OCC)C.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[O:13])=[CH:5]2
Reactant: OCc1cc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=[Mn]=O
Solvent: CCOCC
Product: O=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
A solution of 5,6-dichloroindole-2-methanol (43 g, 199 mmol) in diethyl ether (1.3 l) was treated with activated MnO2 (64 g, 730 mmol) and stirred for 15 hours at room temperature. Additional MnO2 (20 g, 230 mmol) was added and stirring continued for 5 h. The suspension was filtered on a Celite pad, then the pad was washed with diethyl ether and warm acetone. The pooled organic phases were concentrated to give 38.5 g of the title compound (180 mmol, yield 90.4%) that was used as such in the next step, m.p.=207-208° C.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=1
Reactant: COCOc1ccc(C2=CC(=O)CC2)c(OCOC)c1
Solvent: CO
Product: O=C1C=C(c2ccc(O)cc2O)CC1
Yield: 80.5 %

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclopenten-1-one (20 mg) was heated at 50° C. in MeOH (4 ml) containing acidic ion exchange resin (100 mg) for 3 hr. The reaction mixture was filtered and the resin washed with ethyl acetate (20 ml). The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, ethyl acetate/petrol, 7:3 v/v) to furnish 3-(2,4-dihydroxyphenyl)-2-cyclopenten-1-one (11 mg, 79%). 3-(2,4-Dihydroxyphenyl)-2-cyclopenten-1-one (6 mg), hydroxylamine hydrochloride (3.3 mg) and triethylamine (6.6 μl) were heated in ethanol (3 ml) under reflux for 3 hr. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a yellow solid and as one major isomer (4 mg, 62%). Data reported for the major isomer: δH (d4-MeOH) 2.74-2.77 (2H, m), 2.96-2.99 (2H, m), 6.34 (1H, dd), 6.38 (1H, d), 6.96 (1H, t), 7.22 (1H, d); m/z (ES−) 204 (M−H)−.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[F:17][C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:24][CH2:23][O:22][C:21]2[CH:26]=[CH:27][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:10][CH2:11]1
Reactant: Cc1ccc(CC2CCNCC2)c(F)c1
Reactant: Fc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(F)cc3)CC2)c(F)c1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-methylbenzyl)piperidine hydrochloride (375 mg, 1.54 mmol), 2-(4-fluorophenoxy)ethyl bromide (355 mg, 1.62 mmol) and K2CO3 (437 mg, 3.16 mmol) as a colorless crystalline solid (362 mg), mp 167-168° C.; 1H NMR (CDCl3) 1.60-1.80 (m, 3H), 1.95-2.15 (m, 2H), 2.30 (s, 3H), 2.61 (d, J=6.6 Hz, 2H), 2.65-2.83 (m, 2H), 3.20-3.70 (m, 4H), 4.51 (d, J=4.2 Hz, 2H), 6.78-7.00 (m, 7H), 12.60 (bs, 1H); Anal. Calcd for C21H26ClF2NO: C, 66.05; H, 6.86; N, 3.67. Found: C, 66.09; H, 6.78; N, 3.46.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.N#N.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.O>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(O)cc1O
Reaction time: 1.08 h
Yield: 93.8 %

Procedure:
The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol (6.8 L) and water (1.04 L) and after purging with N2 10% Pd/C (90 g) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCl (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60° C. under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06 L) and netralised to pH 7.5-8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2×0.8 L) and dried at 40° C. to constant weight to give the title compound 588 g (94% yield).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:37]([N:36]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:35][CH2:34][N:33]([CH3:44])[CH3:32])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CN(C)CCNCc1ccccc1
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(CCN(C)C)Cc2ccccc2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N,N-Dimethyl-N′-benzyl-ethane-1,2-diamine (62 μL). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 609 (M+H).
Reaction SMILES: [N+](C1C=CC(C=O)=CC=1)([O-])=O.Cl.C[C@@H]1CNCCN1C(OC(C)(C)C)=O.[CH3:27][C@H:28]1[CH2:33][N:32]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)[CH2:31][CH2:30][N:29]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>>[CH3:27][C@@H:28]1[CH2:33][N:32]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)[CH2:31][CH2:30][N:29]1[C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45]
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate hydrochloride using a method similar to that described for D1 in Description 1. MS (ES+): 280.2, 236.3, no molecular ion (MH+) observed
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:5]=2[O:4]1)[CH3:2].S(Cl)([Cl:22])=O>>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([Cl:22])=[O:19])=[CH:16][C:5]=2[O:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@H]1Oc2cc(C(=O)O)ccc2N(C(C)C)C1=O
Product: CC[C@H]1Oc2cc(C(=O)Cl)ccc2N(C(C)C)C1=O

Procedure:
A mixture of (R)-2-ethyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (1.60 g) in thionyl chloride (30 ml) was stirred under reflux for 2 hours. Thionyl chloride was distilled off under reduced pressure to give (R)-2-ethyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbonyl chloride (1.70 g).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[N:4][C:5]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:7]=1[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[C:23]1(C)[CH:28]=CC=C[CH:24]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([C:2]1[C:3]([O:21][CH3:22])=[N:4][C:5]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:7]=1[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:23]=[CH2:24]
Reactant: Cc1ccccc1
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1c(CO[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)nc1OC
Yield: 100 %

Procedure:
A mixture of 3-bromo-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridine (2.51 g, 6.27 mmol), allytributyltin (2.92 mL, 9.41 mmol), tetrakis(triphenylphosphine)palladium(0) (750 mg, 0.627 mmol) and toluene (15 mL) was flushed with nitrogen several times. The reaction mixture was stirred at reflux overnight. The reaction was filtered and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100% hexane to 5% EtOAc/hexane) to yield 3-allyl-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridine (2.62 g, 100%). 1H-NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 5.85 (m, 1H), 4.93-5.11 (m, 2H), 4.74 (s, 2H), 4.04 (s, 3H), 3.37 (d, J=5Hz, 2H), 0.99 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: Br[CH:2]([CH:19](Br)[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=[O:4].ClCCl.CO.N>>[N:13]1([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:11][CH:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Nc1ccc(CN2CCCCC2)cc1)C(Br)C(Br)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 3.4.b. from 2.3-dibromo-3-(4′-chlorobiphenyl-4-yl)-N-(4-piperidin-1-ylmethylphenyl)propionamide. Yield: 26 mg (23.9% of theory); C27H25ClN2O (M=428.96); calc.: molecular ion peak (M+H)+: 429/431; found: molecular ion peak (M+H)+: 429/431; Rf value: 0.42 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[C:7]([CH:12]=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.Br[C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C.C([O-])(O)=O.[Na+].CCOC(C)=O.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>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][CH:32]=[C:23]([C:6]2[C:7]([CH:12]=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:24]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccnc2C=O)c1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
A stirred solution of 3-Tributylstannanyl-pyridine-2-carbaldehyde (256 mg, 0.65 mmol) and methyl 3-bromobenzoate (128 mg, 0.59 mmol) in DMF (2.1 mL) was degassed with Ar for 5 minutes, after which PdCl2(PPh3)2 (25 mg, 0.036 mmol) and CuO (34 mg, 0.43 mmol) was added and the mixture heated to 110° C. overnight. The reaction was cooled to room temperature, and diluted with saturated aqueous NaHCO3 (15 mL) and EtOAc (40 mL). The organic phase was separated, washed with brine (3×15 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 60:40) gave 3-(2-Formyl-pyridin-3-yl)-benzoic acid methyl ester (25 mg, 17%) as a white solid. 1H NMR (CDCl3) δ 3.92 (s, 3H), 7.47-7.56 (m, 2H), 7.58 (d, 1H, J=4.9 Hz), 8.03 (s, 1H), 8.07-8.20 (m, 1H), 8.86 (dd, 1H, J=4.9, 1.8 Hz), 10.08 (s, 1H).
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][O:23][CH:24]([O:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([O:23][CH3:22])[O:32][CH3:33])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Reactant: COC(CCCCCC=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(CCCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1)OC
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a three-necked SOL flask equipped with a mechanic stirrer, a nitrogen inlet, cooling bath and a thermometer was added (S)-3-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.5 kg, 8.93 mol) and dichloromethane (20 L) and this mixture was stirred until the solid dissolved. The reaction mixture was then cooled to 0° C. and 7,7-dimethoxy-heptanal (1.71 kg, 9.82 mol) was added slowly while maintaining the reaction temperature below 5° C. This reaction mixture was stirred at 0 to 5° C. for 1 hr and then sodium triacetoxyborohydride (2.27 kg, 10.72 mol) was added in small portions over 30 minutes while maintaining the reaction temperature below 5° C. The reaction mixture was then stirred at room temperature for 6 hrs. An aqueous 5% potassium carbonate solution (20 L) was then added while maintaining the reaction temperature below 20° C. and the reaction mixture was then stirred for 1 hr at room temperature. The layers were then separated and the organic layer was washed with brine (10 L) and then dried over sodium sulfate (2 kg) for about 3 hrs. After separating the organic layer from the sodium sulfate, the organic layer was concentrated to about 10 L under reduced pressure. This mixture was then purified by silica gel chromatography (40 kg) using the following sequence of eluents: dichloromethane (100 L); 3% MeOH, 97% DCM, as needed; 5% MeOH, 95% DCM, as needed; and 10% MeOH, 90% DCM, as needed. The fractions containing the desired intermediate were then combined (Rf 0.3; 10% MeOH/90% DCM) and concentrated at a temperature less than 30° C. to afford 3.3 kg of the title intermediate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([C:16]1[Se:20][C:19]([C:21]([NH2:23])=[O:22])=[C:18]([NH2:24])[CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(O)(C)C>[C:12]([C:16]1[Se:20][C:19]([C:21]([NH2:23])=[O:22])=[C:18]([NH:24][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ncnc2ncccc12
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Solvent: CC(C)O
Product: CC(C)(C)c1cc(Nc2ncnc3ncccc23)c(C(N)=O)[se]1

Procedure:
As shown in scheme G, 4-chloropyrido[2,3-d]pyrimidine (Robins, R. K. et. al., J. Am. Chem. Soc., 1955, 77, 2256-2260) is reacted with 5-tert-butyl-3-aminoselenophene-2-carboxamide in a protic solvent such as isopropyl alcohol to yield 5-(tert-butyl)-3-(pyridino[3,2-e]pyrimidin-4-ylamino)selenophene-2-carboxamide.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:17]([CH:20]=[CH2:21])[CH2:18]O)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][N:9]([C@H:17]([CH:20]=[CH2:21])[CH2:18][N:26]1[C:22](=[O:32])[C:23]2[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25]1=[O:27])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@H](CO)N(OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C[C@H](CN1C(=O)c2ccccc2C1=O)N(OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
A suspension of (R)-tert-butyl benzyloxy(1-hydroxybut-3-en-2-yl)carbamate (Intermediate 154, 74 g, 252.25 mmol), phthalimide (66.8 g, 454.02 mmol) and triphenylphosphine (119 g, 453.70 mmol) in toluene/THF (200/200 mL) was cooled under nitrogen with ice. DIAD (91.8 g, 453.98 mmol) was added dropwise over 20 minutes and the mixture was stirred at 0° C. for 20 minutes, without cooling for 2 hr. The mixture was filtered and the filtrate was evaporated. The residue was taken up in ether and filtered. The filtrate was evaporated and the residue was purified by silica gel column and eluted with EtOAc/hexane (0-50%) to give the title compound (74 g, 79%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](OC)=[O:15])=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=2)=[C:4]([F:19])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[N:11]=[CH:12][C:13]=2[CH2:14][OH:15])=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2F)c(CO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate (0.32 g, 1.144 mmol) in tetrahydrofuran (10 mL) at −10° C., LAH (1.716 mL, 1.716 mmol) was added portionwise. The reaction mixture was stirred for 2 h at RT then diluted with saturated aqueous NH4Cl (50 mL). The mixture was extracted with ethyl acetate (80 mL). The organic layer was separated, dried over Na2SO4 and concentrated to afford (4-(4-chloro-2-fluorophenyl)-6-methylpyridin-3-yl) methanol (0.25 g, 0.993 mmol, 87% yield) as off-white solid. LCMS (ESI) m/e 252.0 [(M+H)+, calcd for C13H12ClFNO 252.0]; LC/MS retention time (Method H): tR=1.60 min; 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.52 (s, 1H), 7.23 (s, 2H), 7.04-7.17 (m, 1H), 4.57 (d, J=11.60 Hz, 2H), 2.60 (s, 3H).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].O>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([N:6]3[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]/[C:2]/3=[N:1]\[C:29](=[O:31])[CH3:30])[S:8][CH:9]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)/N=C1\OCC(C)(C)N1c1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 4 h
Yield: 64.6 %

Procedure:
4-[2-(2-Imino-4,4-dimethyl-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (0.075 g, 0.25 mmol), prepared in Example 63, was dissolved in tetrahydrofuran (2 mL) followed by triethylamine (0.069 mL, 0.5 mmol) and acetylchloride (0.039 g, 0.5 mmol). The mixture was stirred 4 h, poured into water, extracted with ethyl acetate, and dried over anhydrous MgSO4. The solvent was evaporated and residue triturated with hexane/ethyl acetate (95/5), collected and dried to give the title compound (0.055 g, 64%). HRMS: calcd for C17H16N4O2S+H+, 341.10667; found (ESI, [M+H]+), 341.1075; HPLC purity 96.5% at 210-370 nm, 9.4 min; 96.0% at 250 nm, 9.4 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C@H:10]([C:21]([O:23]C)=[O:22])[CH2:11][NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])=[C:5]([Cl:27])[CH:4]=1.[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1.O.[OH-].[Li+].Cl>O1CCCC1.CN(C=O)C.O.CO>[Cl:27][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][C:32]([C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([OH:28])[CH:30]=2)=[O:33])[CH:26]=[CH:25][C:6]=1[C:7]([NH:9][C@H:10]([C:21]([OH:23])=[O:22])[CH2:11][NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8]
Reactant: O=C(O)c1cccc(O)c1
Reactant: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(CN)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2)C(=O)O)c(Cl)c1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
A mixture of N-(aminomethyl)-2-chlorobenzoyl]-3-benzoylamino-L-alanine (Example 363; 100 mg, 0.26 mmol), 3-hydroxybenzoic acid (40 mg, 0.29 mmol) and dicyclohexylcarbodiimide (60 mg, 0.29 mmol) in tetrahydrofuran/DMF (4:1; 2.5 mL) was stirred at room temperature overnight. Methanol (1 mL) and a solution of lithium hydroxide monohydrate (100 mg, 2.4 mmol) in water (1 mL) were added and the solution was stirred at room temperature overnight. The solution was made acidic with 1 M HCl and extracted with ethyl acetate. The ethyl acetate was evaporated and the residue purified by HPLC to give N-[2-chloro-4-[[(3-hydroxyphenyl) carbonyl]aminomethyl]benzoyl]-3-benzoylamino-L-alanine (12.2 mg, 9%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[C:13]([OH:15])=O.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:15])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: COc1cccc2c1CCCC2C(=O)O
Product: COc1cccc2c1CCCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 14.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.0 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.91 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.48 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)[CH:14]=[CH:13]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)[CH:14]=[CH:13]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(F)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Yield: 59 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-methanone (100 mg, 0.26 mmol), hydroxylamine hydrochloride (55 mg, 0.79 mmol) and sodium carbonate (83 mg, 0.78 mmol) in ethanol (1 ml) was heated under reflux conditions for 17 h, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×75 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and crystallization (ethyl acetate/heptane) to yield the title compound as white solid (61 mg, 59%).