Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O.[CH2:21]([N:23](CC)[CH2:24]C)C.CNC.C1COCC1>C(Cl)Cl>[CH3:21][N:23]([CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[CH3:24]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccccc1-c1nc2ccccn2c1CCl
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)Cc1c(-c2ccccc2N)nc2ccccn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To 3-Chloromethyl-2-(2-nitro-phenyl)-imidazo[1,2-a]pyridine (324 mg, 1.0 mmol) suspended in CH2Cl2 (20 ml) cooled to 0° C. was added dropwise triethylamine (303 mg, 3 eq), followed by 2 M dimethylamine in THF (8 mmol, 4 ml) in two portions over a 5 hour period. The reaction mixture was concentrated to dryness, dissolved in CH2Cl2 (20 ml) washed with water, brine, dried over Na2SO4, concentrated and purified by chromatography using a 9:1 mixture of CH2Cl2 /MeOH. The fractions were concentrated, dissolved in THF (15 ml), and stirred over H2 balloon with 10% Pd/C (10 mg) overnight. The reaction mixture was filtered through Celite and concentrated to obtain the product as a yellow solid (164 mg). (MS, M++H=267.1)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=O.CC([O-])=O.[Na+].Cl.[NH2:19][OH:20]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[N:19][OH:20]
Reactant: NO
Reactant: COc1cc(Cl)cc(Cl)c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A sol. of 2,4-dichloro-6-methoxybenzaldehyde (2.39 mmol) in 5 mL DMF was cooled to 0° C. and NaOAc (2.63 mmol) followed by hydroxylamine HCl (2.63 mmol) were added. The ice bath was removed and the reaction mixture was stirred at RT for 10 min. The mixture was diluted with EtOAc and washed once with water and brine. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give the desired compound as white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:14]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:24])[CH:11]([CH3:13])[CH3:12])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:14]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:24]
Reactant: CC(C)N(CCNC(=O)OC(C)(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To the solution of rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.2 mmol) in DCM (10 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature for 2 hr, then washed with NaOH solution (5%) and water. The organic layer was dried over Na2SO4, concentrated in vacuo to give 60 mg rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=392
Reaction SMILES: [CH2:1]([P:3]1(=[O:25])[CH2:8][CH2:7][N:6]([C:9](=[O:24])[CH2:10][C:11]2[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([P:3]1(=[O:25])[CH2:8][CH2:7][N:6]([C:9](=[O:24])[CH2:10][C:11]2[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCP1(=O)CCN(C(=O)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCP1(=O)CCN(C(=O)Cc2ccc(C(=O)O)cc2)CC1

Procedure:
tert-Butyl 4-[2-(4-ethyl-4-oxido-1,4-azaphosphinan-1-yl)-2-oxoethyl]benzoate (270 mg, 0.739 mmol) was dissolved in CH2Cl2 (8 mL) and TFA (2 mL) and stirred at room temperature for 2 h. The solution was concentrated to dryness, redissolved in MeOH, and concentrated again to give the product as a colorless gum that was carried on without purification. MS: cal'd 310 (MH+), exp 310 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc([C@H](C)c2nccn2C(=O)OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound of Example 58 (7.50 g, 37.4 mmol) and triethylamine (5.74 ml, 41.2 mmol) in dichloromethane (100 ml), cooled in an ice bath, was added dropwise benzyl chloroformate (21.4 ml, 150 mmol). The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 3 h. The mixture was cooled, before addition of aqueous sodium hydrogen carbonate solution and dichloromethane and the two layers were separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried (MgSO4) and concentrated in vacuo. To the residue was added cyclohexane and the solution was filtered and concentrated in vacuo.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH:33][CH2:34][CH:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCC1CCOCC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCC1CCOCC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 68 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-aminomethyltetrahydropyran (available from Aldrich Chemical Company, Inc.; 71 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(tetrahydro-pyran-4-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (81 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.22 (br s, 1H), 8.58 (t, J=5.8 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 3.86 (dd, J=11.2, 2.6 Hz, 2H), 3.27 (t, J=10.9 Hz, 2H), 3.19 (t, J=6.4 Hz, 2H), 1.77-1.87 (m, 1H), 1.61 (d, J=11.3 Hz, 2H), 1.15-1.27 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:32]=1>>[CH3:36][S:33]([C:31]1[CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=[N:29][CH:30]=1)(=[O:35])=[O:34]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CS(=O)(=O)c1cncc(Br)c1
Product: CS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (300 mg, 1.0 mmol) and 3-Bromo-5-methanesulfonyl-pyridine (example B.19) (212 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (350 mg, 68%). MS (ISP) 511.1 [(M+H)+]; mp 241-242° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][C:10](=O)[NH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]2=[N:8][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2c(Cl)nccc2[nH]1
Product: Clc1cnc2c(Cl)nccc2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A suspension of 5-chloropyrido[3,4-b]pyrazin-2(1H)-one (0.57 g, 3.14 mmol) in phosphorus oxychloride (10.24 mL, 110 mmol) was stirred at 110° C. for two hours, and then concentrated. The residue was dissolved in DCM, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (580 mg, 2.90 mmol). MS m/z=200 (M+H)+.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5]([CH:13]2[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=12>CC(O)CC>[NH2:1][C:11]1[N:6]2[C:5]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:4][C:3]([Br:2])=[C:7]2[CH:8]=[N:9][CH:10]=1
Reactant: CC1(O)CC(c2nc(Br)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CCC(C)O
Product: CC1(O)CC(c2nc(Br)c3cncc(N)n23)C1
Temperature: 90 °C

Procedure:
A 35% ammonia solution (132 ml, 2.9 moles) was added to a suspension of 3-(1-bromo-8-chloroimidazo[1,5-α]pyrazin-3-yl)-1-methylcyclobutanol (22.0 g, 0.06463 mol) in 2-butanol (81 ml). The mixture was heated at 90° C. in a pressure vessel for 15 hr then concentrated to 130 ml, cooled to room temperature and the solid collected by filtration. This material was washed with water (3×22 mL) and dried at 40° C. under vacuum. To afford the desired product. 1H NMR (DMSO-d6, 400 MHz): δ 7.5 (d, 1H), 7.0 (d, 1H), 6.6 (bs, 2H), 5.1 (s, 1H), 3.4 (pentet, 1H), 2.3-2.4 (m, 4H) and 1.4 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.S(=O)(=O)(O)O.[CH3:18]O>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:18])=[O:11])=[CH:2]1
Reactant: CO
Reactant: O=C(O)c1c[nH]c2ncccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c2ncccc12

Procedure:
4.22 g (26 mmol) of 1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid were added to 100 cm3 of methanol at a temperature in the region of 20° C. and then 2.5 cm3 of concentrated sulfuric acid were run in dropwise. After stirring at reflux of the solvent for 16 h, the reaction medium was concentrated to dryness under reduced pressure (2.7 kPa). The residue was rapidly added to 50 cm3 of water and the pH was adjusted to 8 by addition of 1N sodium hydroxide. After extracting with 300 cm3 of ethyl acetate, the organic phase was washed with 2 times 100 cm3 of water and then 100 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulfate and then concentrating to dryness under reduced pressure (2.7 kPa), 3.7 g of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate were obtained in the form of a yellow powder. Mass spectrum: EI: m/z=176 M+; base pic: m/z=145 (M−CH3O)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24](Cl)=[O:25])[CH2:20][CH2:19]1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([NH:30][CH2:27][CH2:28][CH3:29])=[O:25])[CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1
Reactant: CCCN
Product: CCCNC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
In a manner analogous to that of Example 1(e) but using 1-[6-Fluoro-2-phenyl-4-quinolinyl]-4-piperidinecarbonyl chloride and propylamine as starting materials the named compound was obtained as off-white needles, mp 196°-198° dec. after recrystallization from methanol.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].CS(O[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=O)=O>CN(C)C=O.O>[NH2:1][C@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Temperature: 25 °C

Procedure:
Sodium azide (7.65 g, 118 mmol) was added to a solution of 1,1-dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-piperidine-1-carboxylate (21.9 g, 78.5 mmol) in dry dimethylformamide (120 mL) and the resultant suspension heated at 70° C. for 48 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted into ethyl acetate. The organic phase was washed two further times with water, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (10:90 to 50:50), to give the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:13][NH:14][CH3:15].O>CN(C)C=O>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc([N+](=O)[O-])c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 g of 5-chloro-2-nitrobenzonitrile was dissolved in 150 ml of dimethylformamide, and 150 ml of a 50% aqueous solution of dimethylamine was added thereto. After cooling the heat generated, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the precipitate thus formed was collected by filtration, washed with water and then with methanol to obtain 64.5 g of 5-dimethylamino-2-nitrobenzonitrile (melting point: 174°-175° C.).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[CH:11][C:10]=1[O:32][CH3:33])C1C=CC=CC=1.[N+](C1C=CC(S([O:46][CH2:47][C@@H:48]2[CH2:50][C:49]2([F:52])[F:51])(=O)=O)=CC=1)([O-])=O>>[F:52][C:49]1([F:51])[CH2:50][C@H:48]1[CH2:47][O:46][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CC2(F)F)cc1
Reactant: COc1cc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)ccc1OCc1ccccc1
Product: COc1cc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)ccc1OC[C@@H]1CC1(F)F

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3-methoxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and ((1S)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Step D of Example 68, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])=[CH:31][CH:30]=1)[CH3:28].Cl>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:38])([CH3:37])[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:27][CH3:28])=[CH:30][CH:31]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(CC(C)(C)N)cc1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: Cl
Product: CCc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1

Procedure:
The target compound is prepared analogously to the method for Example 8(d) from 2.14 g (6.0 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 1.0 g (5.6 mmol) of 2-(4-ethylphenyl)-1,1-dimethylethylamine. White solid. Yield: 1.7 g (54%, hydrochloride); melting point 210° C.-214° C.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[C:14](CC(C(OCC)=O)C(OCC)=O)[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2CCC3C=CC=[C:41]([C:45]([C:50]([O:52][CH2:53][CH3:54])=[O:51])(C)C([O-])=O)C=3SC=2C=1)#N>>[C:1]([C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:41][CH2:45][C:50]([O:52][CH2:53][CH3:54])=[O:51])[C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Cc1ccc2c(c1)CCc1ccc(C#N)cc1S2)C(=O)OCC
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1cccc2c1Sc1cc(C#N)ccc1CC2
Product: CCOC(=O)CCc1cccc2c1Sc1cc(C#N)ccc1CC2
Yield: 97 %

Procedure:
Substituting ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonylpropanoate in the foregoing example with an equivalent amount of ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]-thiepin-4-yl-2-ethoxycarbonylpropanoate provided the title compound in 97% yield. The compound was purified by short-path distillation at an oven temperature of 190°/0.05 Torr and then has m.p. 61°-62° C. Analysis for: C20H19NO2S Requires: C 71.19, H 5.68, N 4.15, S 9.50; Found C 71.13, H 5.80, N 4.09, S 9.42.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([Cl:13])=[CH:4][N:3]=1.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][C:24]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]3[C:5]([Cl:13])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)[CH3:15]
Reactant: OCCCNc1nc(Cl)ncc1Cl
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3Cl)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.5 %

Procedure:
To a solution of 3-[(2-chloro-5-chloro-4-pyrimidinyl)amino]-1-propanol (Example 440, 1.08 g, 4.90 mmol) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 539 mg, 2.45 mmol) in THF (40 mL) were added PPh3 (1.29 g, 4.90 mmol) and ADDP (1.26 g, 4.90 mmol). The reaction mixture was vigorously stirred at rt for 72 h, after which additional amounts of PPh3 (1.29 g, 4.90 mmol) and ADDP (1.26 g, 4.90 mmol) were added. After stirring for an additional 24 h, the reaction mixture was diluted with hexanes, filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was then purified by silica gel chromatography (1:1 hexanes/EtOAc) to give the product (920 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 1.29 (t, 3H), 1.71-1.82 (m, 1H), 2.15 (qt, 2H), 2.35-2.47 (m, 2H), 2.72 (dd, 1H), 2.79-2.98 (m, 2H), 3.48-3.58 (m, 1H), 3.74 (q, 2H), 4.12 (t, 2H), 4.18 (q, 2H), 6.22-6.31 (b, 1H), 6.73 (dd, 1H), 6.79 (d, 1H), 7.08 (d, 1H), 7.25 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:9]=1[N:10]([C@@H:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+](C1C=CC([O:40][C:41](=O)[O:42][CH:43]2[CH:50]3[CH:46]([O:47][CH2:48][CH2:49]3)[O:45][CH2:44]2)=CC=1)([O-])=O.C(N(C(C)C)CC)(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C@@H:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:41]([O:42][CH:43]1[CH:50]2[CH:46]([O:47][CH2:48][CH2:49]2)[O:45][CH2:44]1)=[O:40])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCN
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC2OCCC12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCNC(=O)OC1COC2OCCC12
Reaction time: 1 h

Procedure:
A mixture of crude 3-[[3-Amino-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester in ACN (3.0 mL) was treated with carbonic acid hexahydro-furo[2,3-b]furan-3-yl ester 4-nitro-phenyl ester (0.11 g, 0.375 mmol) followed by diisopropylethyl amine (0.1 mL, 0.625 mmol) and DMAP (cat). The reaction was stirred for 1 h and quenched with CH3OH (1 mL). Solvent was removed under reduced pressure and the crude material was partitioned between EtOAc, and ½ sat NaHCO3(aq). The organics were dried over Na2SO4, solids filtered and solvent removed under reduced pressure. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[3-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-1-(S)-methyl-propyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was isolated by reverse phase HPLC and carried forward wet to the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:23]([CH2:24][NH:25][CH2:26][CH3:27])=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=1)[CH3:2].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:23]([CH2:24][N:25]([CH2:26][CH3:27])[C:46](=[O:47])[CH2:45][O:44][CH3:43])=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc2ccccc2nc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: COCC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)COC)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(3-ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester; dihydrochloride and methoxyacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:29][C:26]1[CH:27]=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCc2ccc(Cl)nc2)c(Cl)c1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a mixture of 0.40 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.21 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a solution of 0.25 g of 6-chloro-3-(chloromethyl)pyridine dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.44 g of 3,5-dichloro-4-(6-chloro-3-pyridylmethyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), m.p. 93.3° C.