Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][OH:18])=[N:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:19]I>C(Cl)Cl>[Si:3]([O:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][O:18][CH3:19])=[N:14][CH:13]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(CO)s1
Reactant: CI
Agent: N#N
Solvent: ClCCl
Product: COCc1ncc(CO[Si](C)(C)C(C)(C)C)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)methanol (1.21 g, 4.65 mmol) in CH2Cl2 (3.0 mL) was treated with MeI (0.35 mL, 5.57 mmol) followed by Ag2O (1.61 g, 6.97 mmol) and the resulting mixture (protected from light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (4:1 hept-EA)=0.27. LC-MS-conditions 07: tR=0.99 min, [M+H]+=273.95.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[CH:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](OC2C=CC=CC=2)=[N:17][C:18]#[N:19])=[CH:11][CH:10]=1>COCCOC>[C:18]([N:17]=[C:16]([O:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)[NH:8][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=1)#[N:19]
Reactant: Nc1ccc(N)nc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: COCCOC
Product: N#CN=C(Nc1ccc(N)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
To a stirred mixture of the crude 2,5-diaminopyridine from Step 1 (0.0719 mol) and 100 ml of ethylene glycol dimethylether, under nitrogen, was added diphenylcyanocarbonimidate (17.1 g, 0.0718 mol) in one portion. This mixture was stirred at room temperature for 5 hours and concentrated in vacuo. The residue was triturated three times with Et2O. The solid residue (17.5 g) was stored under nitrogen until it was chromatographed in two portions: 5.0 g was chromatographed over 1000 ml of silica gel (230-400 mesh) by gravity elution with 5% MeOH/CHCl3 at a rate of 21 ml/minute to give 3.02 g of product; the other 12.5 g was chromatographed over 1000 ml of silica gel in the same manner (a poorer separation resulted at this loading) to give 7.31 g of product. The two lots were combined and crystallized from CH3CN to give 8.32 g (45.8%), m.p. 191°-192.5° C. of the titled product as amber needles. (An additional 0.98 g (5.4%) of dark amber needles was also obtained.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[C:19]([O:22][CH2:23][CH3:24])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27].[CH3:28][O:29][CH2:30][CH2:31][OH:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:32][CH2:31][CH2:30][O:29][CH3:28])=[C:19]([O:22][CH2:23][CH3:24])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27]
Reactant: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: COCCO
Product: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1OCCOC

Procedure:
Following the procedure used to prepare Example 17, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrile (138 mg, 0.34 mmol) and 2-methoxyethanol provides 105 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-(2-methoxyethoxy)3-quinolinecarbonitrile, mp 215-217° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10]([C:12]2([NH2:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)CCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2([NH2:18])[CH2:13][CH2:14][N:15]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1
Reactant: NC1(C(=O)NCc2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NC1(C(=O)NCc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A degassed mixture of 4-amino-piperidine-4-carboxylic acid 4-chloro-benzylamide dihydrochloride (48 mg, 0.13 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (21 mg, 0.12 mmol), triethylamine (126 uL, 0.9 mmol) and n-butanol (1.2 mL) was stirred at 100° C. for 18 h. The solvents were removed by evaporation and the crude mixture was first purified on a SCX-II acid resin, eluting with methanol then 2M ammonia/methanol, and then by preparative TLC, eluting with 10% methanol in dichloromethane, to give 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid 4-chloro-benzylamide (37 mg, 0.096 mmol, 80%). LC-MS (LCT2) m/z 385 [M+H+], R, 2.84 min.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:12][N:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4]1.[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[CH:15]=1.[Cl-].[NH4+]>C(Br)C.O1CCCC1>[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:3]3[CH2:12][N:11]4[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]4)[CH2:5][CH2:4]3)([OH:28])[C:16]=2[CH:15]=1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Reactant: ClC1CCC2CCCCN2C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: OC1(C2CCC3CCCCN3C2)c2ccccc2Sc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
Several drops of ethyl bromide were added to a stirred suspension of 1.29 g. (0.054 g.-atom) of magnesium turnings in 5 ml. of tetrahydrofuran under a nitrogen atmosphere. After the reaction began 9.3 g. (0.054 mole) of 3-chloroquinolizidine in 100 ml. of tetrahydrofuran was added. After the addition was completed the mixture was stirred and refluxed for one hour and cooled to 0° C. To the chilled suspension of the Grignard reagent was added a solution of 12.55 g. (0.051 mole) of 2-chloro-9-thioxanthone in 300 ml. of tetrahydrofuran. The solution was stirred at 24° C. for two hours, poured into aqueous ammonium chloride and extracted with ether. The extracts were washed with water, dried and evaporated to give 2-chloro-9-(3-quinolizidinyl)-9-hydroxythioxanthene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[Cl:22]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([Cl:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3.48 g (11.2 mmol) of 3-methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester [prepared from 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 1A) by reaction with 3-chloro-perbenzoic acid in analogy to the procedure described for the preparation of intermediate 1C] was added at RT while stirring to 20.4 ml=34.25 g (223.3 mmol) of phosphorus oxychloride and the reaction mixture was warmed up to 50° C. After 2 hours, it was cooled down to RT and poured into crashed ice. This solution was carefully neutralized with solid sodium carbonate and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/CH2Cl2 1:1 to 0:1) to give 2.52 g (68%) 6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester as light yellow oil; [MS: 330.0 (MH+, 1Cl)] and 1.10 g (30%) 4-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester as colorless solid. MS: 330.0 (MH+, 1Cl).
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]2([CH2:9][O:8][C:7]([CH2:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])([CH3:10])[CH2:6][CH2:5][CH2:4]2)[O:2]1>C(Cl)Cl.N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH2:18]1[CH2:1][O:2][C:3]2([CH2:9][O:8][C:7]([CH3:10])([CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[CH2:6][CH2:5][CH2:4]2)[O:17]1
Reactant: CC(O)CCCC1(C)CCCC2(CO1)OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CCCC1(C)CCCC2(CO1)OCCO2
Yield: 64 %

Procedure:
Dry celite (30 g) and 6,6-ethylenedioxy-2-(4'-hydroxypentyl)-2-methyloxepane (3.3 g, 0.0128 mol) in methylene chloride (50 ml) are added to a pyridine-chromium trioxide solution [prepared from pyridine (12.1 g, 0.153 mol) and chromium trioxide (7.67 g, 0.0767 mol)] in distilled methylene chloride (450 ml) at 10° C. in a nitrogen atmosphere. After 5 hours the mixture is filtered and the celite cake is washed with methylene chloride (10×50 ml). The solvent is removed at reduced pressure. The residue is diluted with ether (150 ml), filtered and the solvent is removed at reduced pressure. The crude product (3.3 g) is chromatographed on SilicAR CC-7 (60 g)in hexane. Elution with 12% ethyl acetate/hexane gives 6,6-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-oxepane as a clear colorless oil (2.1 g, 64%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][C:29]=3I)[CH2:26][CH2:25][CH2:24]4)[C@@H:15]([CH3:31])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]([C:38]1[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42](B(O)O)[CH:43]=1)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][C:29]=3[C:42]3[CH:43]=[C:38]([C:34]([CH3:35])([CH3:37])[CH3:36])[CH:39]=[CH:40][C:41]=3[O:47][CH3:48])[CH2:26][CH2:25][CH2:24]4)[C@@H:15]([CH3:31])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(C)(C)C)cc1B(O)O
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2c(cc1I)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@@H]1C)CCC2

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(6-iodo-2,3-dihydro-1H-inden-5-yl)methyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 25; 25 mg; 0.043 mmol) was treated with (5-tert-butyl-2-methoxyphenyl)boronic acid (11.6 mg; 0.056 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (2.8 mg; 0.0043 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) as described in Example 38 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(5-tert-butyl-2-methoxyphenyl)-2,3-dihydro-1H-inden-5-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a clear glass. LCMS=620.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.84-7.82 (m, 2H), 7.75 (s, 1H), 7.36 (dd, J=8.5, 2.6 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.22 (d, J=15.4 Hz, 1H), 5.13 (d, J=10.3 Hz, 1H), 4.22 (d, J=15.5 Hz, 1H), 3.81 (s, 3H), 3.41-3.32 (m, 1H), 2.99-2.93 (m, 4H), 2.24-2.20 (m, 1H), 2.16-2.11 (m, 2H), 1.82-1.75 (m, 1H), 1.31 (s, 9H), 1.02 (d, J=6.1 Hz, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]([C:9](=[CH2:13])[C:10]([O-:12])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>CO>[Si:5]([O:6][C@@H:7]([C@@H:9]1[CH2:13][N:23]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:10]1=[O:12])[CH3:8])([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:15])[CH3:14]
Reactant: C=C(C(=O)[O-])C(C)O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: COc1ccc(CN2C[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.6 %

Procedure:
To a solution of ethyl (2-[1-(t-butyldimethyl-silyloxy)ethyl]acrylate (5 g) in methanol (100 ml) was added 4-methoxybenzylamine (2.65 g) at room temperature. After two days, the solvent was evaporated and the residual methanol was azeotropically removed using toluene. To the residual product was added tetrahydrofuran (387 ml) and the solution was stirred at room temperature. To this solution was added dropwise mesitylmagnesium bromide in tetrahydrofuran (1M, 31 ml) at room temperature. After stirring for 30 minutes, the reaction mixture was quenched with water and evaporated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The resultant solution was evaporated and the residue was column-chromatographed on silica gel (eluent : a mixture of hexane and ethyl acetate, 3:1) to give (3S*)-3-[(1R*)-1-(t-butyldimethylsilyloxy)ethyl]-1-(4-methoxybenzyl)azetidin-2-one (4.5 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:1][N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)CCc1ccc(-c2ccc(CN3CCN(C)CC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Ethyl 3-[4′-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]propanoate (1 g, 2.7 mmol) was dissolved in dichloroethane (20 mL). At 0° C., acetic acid (0.02 mL, 0.4 mmol) was added, followed, by N-methylpiperazine (0.3 g, 3 mmol) and sodium triacetoxyborohydride (0.86 g, 4 mmol) portionwise. The mixture was stirred at room temperature overnight. At 0° C., saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 0.98 g (80%) of the desired product as a brown oil used in the following step without further purification.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH:14]=[O:15])[C:12]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[I-].[K+]>[CH2:1]([O:19][C:12]1[C:11]([O:10][CH3:9])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C=O)c1OCc1ccccc1
Temperature: 70 °C
Yield: 81 %

Procedure:
Benzyl bromide (8.6 ml) was added to a stirred solution of 3-methoxysalicylaldehyde (10 g), potassium carbonate (14.76 g) and potassium iodide (0.12 g) in DMF (120 ml) under an atmosphere of argon. The reaction was heated at 70° C. for 16 hours. Water (200 ml) was added causing the precipitation of a brown oil which crystallised on cooling. The solid was filtered, washed with water, dissolved in dichloromethane and dried (MgSO4). The solvent was removed in vacuo to give an oil which crystallised on trituration with iso-hexane to give the product as an off white solid (12.85 g, 81%); NMR d (CD3SOCD3) 3.91 (s, 3H), 5.15 (s, 2H), 7.14-7.22 (m, 2H), 7.29-7.42 (m, 6H), 10.10 (t, 1H); M/z (+) 243 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:23])[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[N:9]=[C:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:11]=1[OH:12])=[O:5])C.[NH2:24][C:25]1[CH:29]=[C:28]([Cl:30])[S:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>>[Cl:30][C:28]1[S:27][C:26]([S:31](=[O:33])(=[O:32])[NH2:34])=[C:25]([NH:24][C:4]([C:6]2[C:7](=[O:23])[N:8]([CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[N:9]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:11]=2[OH:12])=[O:5])[CH:29]=1
Reactant: CCOC(=O)c1c(O)c(-c2cccs2)nn(CCC(C)C)c1=O
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Product: CC(C)CCn1nc(-c2cccs2)c(O)c(C(=O)Nc2cc(Cl)sc2S(N)(=O)=O)c1=O
Temperature: 160 °C
Reaction time: 0.17 h

Procedure:
The ester (13a) made by Method 4 (86 mg, 0.26 mmol) and 3-Amino-5-chloro-thiophene-2-sulfonic acid amide (14b) (54 mg, 0.26 mmol) were mixed in a reaction vial and stirred in a preheated oil-bath at 160° C. for 10 mins to give the corresponding 5-hydroxy-2-(3-methyl-butyl)-3-oxo-6-thiophen-2-yl-2,3-dihydro-pyridazine-4-carboxylic acid (5-chloro-2-sulfamoyl-thiophen-3-yl)-amide (15a) as a dark yellow solid which was used directly in next step without further purification. LC-MS (ESI+): m/e=503.09 [M+1]+(exact ms: 502.02).
Reaction SMILES: C([O:4][C:5]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:10][C:9]=2[CH:8]=[CH:7][C:6]=1[O:28][CH3:29])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH3:29][O:28][C:6]1[C:5]([OH:4])=[C:15]2[CH2:14][CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:10][C:9]2=[CH:8][CH:7]=1
Reactant: COc1cc(C2=Cc3ccc(OC)c(OC(C)C)c3CCC2)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1O)CCCC(c1cc(OC)c(OC)c(OC)c1)=C2
Reaction time: 0.17 h
Yield: 41 %

Procedure:
41 (220 mg, 0.55 mmol) was dissolved in 15 mL of anhydrous dichloromethane under nitrogen at room temperature. Aluminium chloride (147 mg, 1.1 mmol) was added and the reaction mixture was stirred for 10 minutes. 10 mL of water was added and the product was extracted in dichloromethane (2×20 mL) and the combined organic phases were dried over anhydrous sodium sulfate, evaporated under reduced pressure purified by column chromatography. The product 3, 81 mg (41% yield) was obtained in 10% ethylacetate in hexanes. Rf: 0.54 (60:40 Hex:EA).
Reaction SMILES: [C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21])([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][NH2:30])[CH3:26]>>[C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19][S:20]([NH:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])(=[O:22])=[O:21])([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CN(C)CCCN
Reactant: O=S(=O)(Cl)CCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Product: CN(C)CCCNS(=O)(=O)CCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Temperature: 75 °C
Yield: 87.2 %

Procedure:
C3F7OCF2CF2CH2CH2SO2Cl (100 g, 0.242 mol, 66.8% in toluene) was added dropwise to a mixture of dimethylaminopropylamine (DMAPA) at 45° C. After the addition, the reaction was heated at 75° C. overnight. The reaction mass was filtered and the wet cake was washed with 60° C. toluene. After stripping off the toluene, the concentrated organic product was washed with 200 mL of 95° C. deionized water. The product Intermediate 1, C3F7OCF2CF2CH2CH2SO2N(H)—CH2CH2CH2N(CH3)2 (101 g, 87.2%) was obtained as an amber colored solids after removing water under reduced pressure.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=O)[CH3:3].[NH:20]1[CH2:25][CH2:24][CH:23]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][CH2:21]1>>[CH2:13]([O:12][C:10]([NH:9][C@H:5]([C:6]([N:20]1[CH2:21][CH2:22][CH:23]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:25]1)=[O:8])[CH2:4][CH:2]([CH3:1])[CH3:3])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC(OCC(=O)OC(C)(C)C)CC1
Yield: 95.4 %

Procedure:
By coupling 2.6 g of Z-L-leucine with 2 g of t-butyl 4-piperidinyloxyacetate as described in Example 1d) there are obtained 4.1 g of t-butyl [[1-[N-[(benzyloxy)carbonyl]-L-leucyl]-4-piperidinyl]oxy]acetate, MS (FAB): 463 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[ClH:2].[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH:20][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(O)c(C)cc3F)c2cc1OC
Yield: 62.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (2.5 g, 9.6 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 2-fluoro-5-hydroxy-4-methylaniline (1.48 g, 10.5 mmol) in isopropanol (150 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6,7-dimethoxyquinazoline hydrochloride (2.2 g, 71 %).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][N:9]1[N:13]=[N:12][C:11]([C:14]2[CH:34]=[C:33]([CH3:35])[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH:22]([C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][N:27]=4)O)=[C:16]([CH3:36])[CH:15]=2)=[N:10]1.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:8][N:9]1[N:13]=[N:12][C:11]([C:14]2[CH:34]=[C:33]([CH3:35])[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:16]([CH3:36])[CH:15]=2)=[N:10]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1cc2cccnc2[nH]1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCCc1cc2cccnc2[nH]1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
Triethylsilane (5 ml) was added to a stirred solution of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-hydroxy-butyl]-7-azaindole (520 mg, 1.33 mmol) in 20 ml of trifluoroacetic acid at 20° C. under nitrogen. The mixture was stirred at 20° C. for 10 min and then stirred at 70°-75° C. for 16 h. To the mixture was added water, and basified with an aqueous sodium bicarbonate solution (to pH=8) followed by extraction with methylene chloride (3×). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (7.5 cm column, ethyl acetate/hexane, 1/5-8/1). The mixture was recrystallized to afford 349 mg (74%) of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-butyl]-7-azaindole, as a white solid, m.p.147°-150° C.
Reaction SMILES: [CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[CH2:23]1>C1(C)C=CC=CC=1>[CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[CH2:23][C:24]4[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=4[C:26]([OH:28])=[O:27])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1
Yield: 71.3 %

Procedure:
A solution of 2.1 g of (E)-3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]benzeneamine, 1.25 g of homophthalic anhydride and 30 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 2.31 g of (E)-2-[2-[3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 189°-190° C. from tetrahydrofuran.