Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:25][C:24](=O)[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH:37]=[CH:36][N:35]=[C:34]3[CH3:38])[CH:28]=2)[O:21]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][C:9]=1[NH:17][C:24](=[O:25])[CH2:23][C:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH3:38])[CH:28]=1)=[O:21])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nccn1-c1cccc(C2=CC(=O)OC(C)(C)O2)c1
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(C(C)C)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G47) and 2,2-dimethyl-6-[3-(2-methyl-imidazol-1-yl)-phenyl]-[1,3]dioxin-4-one (Example J15) according to the general procedure K. Obtained as a yellow oil (186 mg).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[CH:4]=1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[Br:10][C:5]1[CH:4]=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:7]([Br:9])[CH:6]=1
Reactant: [O-]B([O-])Oc1cc(Br)cc(Br)c1
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Brc1cc(Br)cc(-c2ccccc2)c1
Yield: 72.8 %

Procedure:
Suspended in 32 ml of 1,2-dimethoxymethane were 3.0 g (11 mmol) of 3,5-dibromophenyl borate, 2.2 g (11 mmol) of iodobenzene and 0.25 g (0.21 mmol) of tetrakis(triphenylphosphine)palladium, and a solution prepared by dissolving 3.4 g (32 mmol) of sodium carbonate in 16 ml of water was added thereto and refluxed for 9 hours under argon atmosphere by heating. The reaction solution was separated into two layers, and then the organic layer separated was washed in order with 5% sodium carbonate, 5% hydrochloric acid, water and saturated brine and dried on anhydrous sodium sulfate. After the organic solvent was distilled off under reduced pressure, the residue was refined by silica gel chromatography (only hexane) to obtain 2.5 g (yield: 75%) of 3,5-dibromobiphenyl (5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](I)[CH:10]=1)[C:5]([O-:7])=[O:6].[C:12](=O)([O-])[O-].[Cs+].[Cs+].[S:18]1(=[O:25])(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:7][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][S:18]2(=[O:25])=[O:24])[CH:10]=[C:2]([Br:1])[CH:3]=1
Reactant: O=S1(=O)CCCCN1
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])c1cc(Br)cc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(N2CCCCS2(=O)=O)c1
Temperature: 10 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a sealable tube equipped with a stir bar were added 3-bromo-5-iodobenzoate (2.0 g, 5.88 mmol), cesium carbonate (2.85 g, 8.82 mmol), tris(dibenzylideneacetone)dipalladium (0) (27.1 mg, 0.029 mmol) and xant phos (51 mg, 0.088 mmol) in toluene (45 mL) followed by [1,2]thiazinane 1,1-dioxide (902 mg, 6.47 mmol). The resulting mixture was stirred at 10° C. for 16 h, cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude mixture was purified by reverse phase prep HPLC to give the title compound (1.7 g, 84% yield): 1H NMR (CD3OD, 500 MHz) δ ppm 1.93-1.97 (2H, m), 2.30-2.35 (2H, m), 3.30 (2H, t, J=5 Hz), 3.78 (2H, t, J=5 Hz), 3.94 (3H, s), 7.76 (1H, m), 7.93 (1H, m), 8.06 (1H, m). HPLC retention time: 1.772 min (method A). MS (ESI) (M+H)+ 348.06.
Reaction SMILES: C([O-])(O)=O.[Na+].[Br:6][C:7]1[CH:23]=[CH:22][C:10]2[NH:11][C:12](=[O:21])[CH2:13][C:14](=[CH:17]N(C)C)[C:15](=O)[C:9]=2[CH:8]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:34][C:35]([NH2:37])=[NH:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[Br:6][C:7]1[CH:23]=[CH:22][C:10]2[NH:11][C:12](=[O:21])[CH2:13][C:14]3[CH:17]=[N:37][C:35]([NH:34][C:28]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=4)=[N:36][C:15]=3[C:9]=2[CH:8]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Reactant: COc1ccc(NC(=N)N)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(Br)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to method I (NaHCO3 used instead of K2CO3), 7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-k) and 1-(3,4-dimethoxyphenyl)-guanidine were converted to I-18 (74%): HRMS Calcd. for C20H17BrN4O3: 441.0562, Found 441.0548.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:26]([O:27][C:28](OC4C=CC=CC=4)=[O:29])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:37])=[N:15]2)=[CH:10][CH:9]=1.C(OC(C)C)(C)C>C(#N)C>[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:26]([O:27][C:28]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[O:29])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:37])=[N:15]2)=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Yield: 47 %

Procedure:
Anhydrous piperazine (5.15 g.) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (5.2 g.) in acetonitrile (32 cc.). The reaction mixture is stirred for 1 hour at a temperature of about 20° C. and diisopropyl ether (150 cc.) is then added. The insoluble product is filtered off and washed with a mixture (20 cc.) of acetonitrile and diisopropyl ether (50--50 by volume) and then with diisopropyl ether (50 cc.). After recrystallisation of the product thus obtained from a mixture (160 cc.) of acetonitrile and methanol (90--10 by volume), 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(piperazin-1-yl)carbonyloxy-isoindolin-1-one (2.4 g.), melting with decomposition at 245° C., is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([OH:20])=O)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>CN(C=O)C.O>[CH2:26]([NH:33][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:6]([OH:25])=[C:7]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:8]=1)=[O:20])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)c1cc(Nc2ccccc2C(=O)O)cc(C(C)(C)C)c1O
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(Nc2ccccc2C(=O)NCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 1 g quantity of 2,6-di-tert-butyl-4-(2-carboxyphenylamino)phenol (Compound 25) was dissolved in 20 ml of DMF. To the solution were added with ice-cooling 340 mg of benzylamine and 570 mg of DEPC and then added a solution of 330 mg of triethylamine in 5 ml of DMF over 20 minutes. Then the reaction mixture was stirred at room temperature for 20 hours, and then poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4 and concentrated to give a crude product which was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:10→1:5), giving 1.1 g of the title compound as white crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Br-:1].[C:7]([CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:4][CH2:3][CH2:2][P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([OH:9])=[O:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)C(CCCCBr)c1ccccc1
Solvent: CC#N
Product: O=C(O)C(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 100 °C
Yield: 66.7 %

Procedure:
6-Bromo-2-phenylhexanoic acid (16 g, 59 mmole) and triphenylphosphine (20 g, 76 mmole) were dissolved in acetonitrile (100 ml), and the solution was heated at 100° C. for 18 hours. After the completion of the reaction, the solution was cooled and the solvent removed under reduced pressure. The residue was washed three times with toluene, whereby crystals separated out. The crystals were recrystallized from ethyl acetate to give 5-carboxy-5-phenylpentyltriphenylphosphonium bromide (21 g, 67%, m.p. 210°-215° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[F:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([F:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: FC1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC(F)CC5)c34)cc2Cl)cn1
Yield: 43 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and 4-fluoropiperidine to give the title compound in 43% yield; NMR Spectrum: 1.66-1.70 (m, 2H), 1.80-1.87 (m, 2H), 2.41-2.44 (m, 2H), 2.45 (s, 3H), 2.64-2.68 (m, 2H), 2.83 (t, 2H), 4.44 (t, 2H), 4.65 (dm, 1H), 7.20 (d, 1H), 7.25 (br s, 2H), 7.73 (d, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 498 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[NH:4][C:3]1=[O:14].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[S:32](Cl)(=[O:34])=[O:33]>>[NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:32]([C:25]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=2[O:23][CH3:22])(=[O:34])=[O:33])[C:3]1=[O:14]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc(OC)cc1OC

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 2,4-dimethoxybenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/ hexane/iso ether mixture. M.p.=196°-198° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@@H:37]([CH2:40][CH2:41][CH3:42])[NH:36]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@@H:37]([CH2:40][CH2:41][CH3:42])[N:36]1[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[N:6]1)[CH2:33][CH3:34]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCC[C@@H]1CC[C@H](CCC)N1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H]1CC[C@H](CCC)N1C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid from the Step E Example 44 in 1 mL DMF was added 23.0 mg HOBt, 23.3 mg cis-2,5-dipropylpyrrolidine from the Step A above, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 70-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.50 min. (m/Z=428.4, 450.3).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][CH2:21][CH3:22])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:23])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl>CN(C=O)C>[CH2:21]([O:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:23][CH2:30][C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[CH3:33])=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:22]
Reactant: Cc1ccccc1CCl
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4C)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (750 mg, 2.39 mmol) was dissolved with heating in DMF (50 mL). Solid cesium carbonate (1.55 g, 4.77 mmol) was added. After 15 minutes, 2-methylbenzyl chloride (487 mg, 2.63 mmol) was added to the mixture. The reaction was stirred overnight at ambient temperature, then was poured onto water (500-750 mL) and a milky white precipitate formed immediately. The mixture was stirred for 1 hour, and then the precipitate was isolated by filtration. The solid was purified by flash chromatography (silica gel, gradient elution with 0.5-2% methanol in chloroform) followed by recrystallization from 2-propanol. The final product was isolated by filtration and dried overnight under vacuum at 60° C. to provide 780 mg of 2-(ethoxymethyl)-7-[(2-methylbenzyl)oxy]-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off white solid, mp 216.0-218.0° C.
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNCC(C)C.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([O:77]CC3C=CC=CC=3)=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH:70]([CH3:72])[CH3:71])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1>>[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([OH:77])=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH:70]([CH3:71])[CH3:72])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1
Reactant: CC(C)CN1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Agent: CC(C)CNCC[C@H](C)N
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: Cl
Product: CC(C)CN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 68 %

Procedure:
In a similar manner to that described in example Z-35, from 16 (16 mg, 0.035 mmol) and [(3S)-3-Aminobutyl](2-methylpropyl)amine bis-hydrochloride (20 mg, 0.0925 mmol), (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid. This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a tan solid (13 mg, 68% 2 steps). 1H NMR (CDCl3) δ 12.57 (s, 1H), 10.46 (s, 1H), 8.27 (s, 1H), 7.32 (m, 2H), 6.99 (m, 2H), 4.98 (m, 1H), 4.63-4.54 (m, 4.45 (m, 1H),4.26-4.16 (m, 2H), 2.91 (m, 1H), 2:77 (m, 1H), 2.24 (m, 1H), 2.14-2.03 (m, 2H), 1.63 (m, 1H), 1.48 (m, 1H), 1.33 (m, 3H), 1.09 (m, 1H), 0.850 (m, 3H), 0.789 (m, 3H); ES+ MS: 457 (M+1).
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(Cl)(Cl)Cl.CCO>N1C=CC=CC=1>[CH3:36][S:37]([O:35][C@@H:23]1[C@@H:22]([CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)(=[O:39])=[O:38]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 24 h

Procedure:
The product of Example 1 (59 g, 0.13 mol) was dissolved at room temperature in 120 mL of pyridine. The solution was put into an ice bath and 29 mL of methanesulfonyl chloride (0.34 mol) was added dropwise. The resulting solution was allowed to stir at 4° C. for 24 hours. The reaction mixture was added in three portions at a slow flow rate into a blender as described previously. The pea-green solid was collected by filtration, washed twice with 2 L of water, and dried to yield 58 g (93%). The compound started to soften at 85° C. and melted at 106-108° C. Rf =0.62 (CHCl3 --EtOH, 10:1). Anal. (C29H28N2O7S).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C1C=C(NC(N[C@H]([C@@H]2C[C@@H]3CCN2C[C@@H]3CC)C2C3C(=CC=C(OC)C=3)N=CC=2)=S)C=C(C(F)(F)F)C=1.[Cl-].[NH4+].[N+:74]([CH3:77])([O-:76])=[O:75]>>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C@@:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([CH2:77][N+:74]([O-:76])=[O:75])[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccnc2ccc(OC)cc12
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 60 h
Yield: 77 %

Procedure:
4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.0928 g, 0.198 mmol) and 1-[3,5-bis(trifluoromethyl)phenyl)-3-{(S)[(2S,4S,5R)-5-ethyl-1-aza-bicyclo[2.2.2]oct-2-yl]-(6-methoxy-4-quinolinyl)methyl}thiourea (0.0121 g, 0.020 mmol) were dissolved in nitromethane (0.6 ml) and the resulting solution was stirred at 50° C. for 2.5 days. The reaction mixture was cooled to room temperature and aqueous saturated ammonium chloride was added. The resulting mixture was extracted with dichloromethane (3×) and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.080 g, 77%) as a beige solid. Chiral HPLC analysis (Chiralpack AS-RH, MeCN:MeOH:H2O=75:5:20, 1 ml/min, retention time 3.26 minutes (major enantiomer), 2.86 minutes (minor enantiomer) indicated that the reaction proceeded with 97.4% enantioselectivity.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C([O:18][CH:19]=[C:20]([C:26]#[N:27])[C:21](OCC)=O)C>O1CCCC1>[NH:5]1[C:26]([C:20]2[C:19](=[O:18])[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][CH:21]=2)=[N:27][N:7]=[N:6]1
Reactant: Nc1ccccn1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Yield: 15.4 %

Procedure:
Aluminum chloride (1.73 g., 12.96 mmoles) was added to tetrahydrofuran (45 ml.) at -20°. Sodium azide (2.52 g., 38.71 mmoles) was then added and the mixture heated under reflux for 40 minutes. To this mixture was added 2-aminopyridine (1.0 g., 10.62 mmoles) and ethyl ethoxymethylenecyanoacetate (1.8 g., 10.62 mmoles). The mixture was heated under reflux for 18 hours. The mixture was concentrated and the residue treated with water (50 ml.). The mixture was acidified to pH 3 with 6N hydrochloric acid. The solid material was collected and suspended in 3% aqueous sodium bicarbonate. The mixture was heated under reflux for 5 minutes, filtered, and the filtrate acidified to pH 4 with 6N hydrochloric acid. The precipitate was recrystallized from N,N-dimethylformamide to give the title compound (0.35 g., 15.4%), m.p. 312°-313° (decomp).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].CC(OC(C)=O)=O>CCOCC>[CH2:1]([N:8]1[C:12]([NH2:13])=[CH:14][C:15](=[O:16])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)O
Reactant: NC(=O)NCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Temperature: 77.5 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of benzylurea (33.3 mmol), 2-cyanoacetic acid (36.63 mmol) and Ac2O (20 mL) was heated at 75-80° C. for 2 hours. After cooling to room temperature, 30 mL of Et2O was added and the resultant suspension was stirred for 1 h. The solid intermediate was filtered, suspended in a mixture of water (30 mL) and ethanol (15 mL) and heated at 80-85° C. 5 mL of 10% NaOH were slowly added. After 30 minutes, the reaction mixture was concentrated, acidified with 10% HCl and the precipitate collected by filtration (Yellow solid. Yield 70-80%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([N:28]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH3:30])(C)C>C1(C)C=CC=CC=1>[CH2:9]([N:28]([CH2:29][CH2:30][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:2])[C:31]1[CH:32]=[CH:11][CH:10]=[CH:9][CH:33]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCI
Reactant: Nc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)c1ccccc1
Temperature: 100 °C
Yield: 48 %

Procedure:
Aniline (0.93 g), 1-iodohexadecane (10.56 g) and diisopropylethylamine (2.58 g) were combined in 10 ml of toluene. The mixture was heated at about 100° C. for a period of three days. The mixture was chromatographed on a silica gel column using 1% ethyl acetate in hexane. The heavy crystalline mass that precipitated from solution was cooled, diluted with ether and filtered. The filtrate was concentrated to an oil and applied to a silica gel column. The oil was washed with 500 ml of hexane followed by 1% ethyl acetate in hexane. The dialkylated fractions were combined and evaporated to give 2.6 grams of product.