Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[C:5]2[OH:15].S(Cl)(Cl)=O.[C:20](OCC)(=O)C>CO>[CH3:20][O:13][C:12]([C:7]1[CH:6]=[C:5]([OH:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: O=C(O)c1cc(O)c2cc(F)ccc2c1
Reactant: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(O)c2cc(F)ccc2c1
Yield: 28 %

Procedure:
To a solution of 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid (0.500 g, 2.42 mmol) in MeOH (10 mL) was added thionyl chloride (0.265 ml, 3.63 mmol) drop-wise at 0° C. and the resulting mixture was refluxed for 5 hours. Methanol was distilled off under reduced pressure, and the residue was diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with water (5 mL) followed by brine (5 mL), dried and concentrated under reduced pressure to obtain the crude product. Silica gel column chromatography (5% ethyl acetate in hexanes) afforded 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid methyl ester (0.150 g, 28%) as a light yellow solid. MS cald. for C12H10FO3 [(M+H)+]: 221, obsd. 221.2.
Reaction SMILES: [Mg].C(I)C.II.Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1.S(=O)(=O)(O)O>C1COCC1>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[CH2:23])=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Cc1ccc(Br)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCI
Product: C=C(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Into a 1-liter reaction flask were introduced in a nitrogen stream 15.6 g (0.65 mol) of magnesium and 20 ml of THF. Slight amounts of ethyl iodide and iodine were added thereto to initiate reaction. A solution of 111.15 g (0.65 mol) of p-bromotoluene in 500 ml of THF was then added dropwise at room temperature to 40° C. over a period of 2 hours to prepare a Grignard reagent. Thereto was added dropwise a solution of 83.75 g (0.625 mol) of p-methylacetophenone (10a) in 200 ml of THF at that temperature over a period of 3 hours. This mixture was stirred first at room temperature for 3 hours and then with refluxing for 4 hours. The resulting reaction mixture was cooled and poured into 1 liter of 5% aqueous sulfuric acid solution to conduct hydrolysis. This mixture was extracted with toluene, and the extract was washed with aqueous soda ash solution and then with water and concentrated. Thereto were added 300 ml of toluene and 0.5 g of PTSA. The resulting mixture was stirred with refluxing for 4 hours to conduct azeotropic dehydration, followed by washing with aqueous soda ash solution, washing with water, and concentration. The resulting crude 1,1-di(p-tolyl)ethylene (9b) was distilled with a Claisen flask equipped with a vigreux, giving 98.5 g of the desired compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CO>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCCBr)cc1
Yield: 17.9 %

Procedure:
To a solution of hydroquinone (2.0 g, 18.2 mmol) in MeOH (10 mL), KOH (1.02 g, 18.2 mmol) was added. Then 1,5-dibromopentane (3.1 mL, 22.7 mmol) was added dropwise over 10 min and the mixture was refluxed for 12 hours. The reaction mixture was concentrated, quenched with water (100 mL), and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed water, brine, and dried over Na2SO4. The compound was purified by column chromatography to isolate intermediate 13a as a colorless oil (0.94 g, 3.26 mmol, 20% yield). 1H NMR (CDCl3, 400 MHz) δ 6.76-6.84 (m, 4H), 4.50 (s, 1H), 3.93 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H), 1.92-1.96 (m, 2H), 1.77-1.84 (m, 2H), 1.60-1.67 (m, 2H).
Reaction SMILES: O.Cl.C(=[N:16][CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:18]#[N:19])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C>[NH2:16][CH:17]([CH2:20][C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)[C:18]#[N:19]
Reactant: N#CC(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#CC(N)Cc1ccncc1
Reaction time: 0.5 h

Procedure:
To a solution of ethanol (10 mL), water (0.09 mL, 5 mmol), hydrogen chloride (9.6 mL, 1M in diethyl ether) was added a solution of 2-(benzhydrylidene-amino)-3-pyridin-4-yl-propionitrile (1.50 g, 5 mmol) in ethanol (10 mL). The reaction was stirred for 30 minutes, then concentrated to one third volume. The crude residue was triturated with five 30 mL portions of hexane:ether (4:1 vol:vol) and seven 30 mL portions of hexane. The precipitate was dried in vacuo to give 2-amino-3-pyridin-4-yl-propionitrile as an off white powder (1.05 g, 99%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1([CH2:19][O:20][N:21]2[C:27](=[O:28])[N:26]3[CH2:29][C@H:22]2[CH2:23][CH2:24][C@H:25]3[C:30]([OH:32])=[O:31])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:19]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([O:32][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:37][CH2:36]1)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (69.6 mg, 0.57 mmol) were added sequentially to a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (105 mg, 0.38 mmol) in dry dichloromethane at room temperature. tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (123 mg, 0.57 mmol) was then added and the reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([NH:26][C@@H:27]([CH2:31][NH2:32])[C:28]([OH:30])=[O:29])=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C1COCC1.[OH-].[Na+]>[CH:18]1[C:19]2[CH:20]([CH2:22][O:23][C:24]([NH:26][C@@H:27]([CH2:31][NH:32][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:28]([OH:30])=[O:29])=[O:25])[C:21]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CNC(=O)C1CCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopentanecarbonyl chloride (81 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (142 mg, 54%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:7]([O:19][CH3:20])[CH:6]=1)[OH:4].[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=3)=[C:7]([O:19][CH3:20])[CH:6]=2)[C:2]([F:1])([F:21])[F:22])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: COc1cc(C(O)C(F)(F)F)ccc1Oc1cccc(F)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)ccc1Oc1cccc(F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
To a solution of 2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethanol (0.52 mmol; 165 mg), tosyl chloride (0.57 mmol; 109 mg) and DMAP (0.01 mmol; 1.5 mg) under argon in dichloromethane (4 mL) at 0° C. was added TEA (1.04 mmol; 145 μl). The reaction mixture was stirred at rt for 3 h, then washed with brine (2×), dried over MgSO4, concentrated and purified by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70) to yield the title compound (101 mg; 0.21 mmol; 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:28]([CH:36]=O)[NH:27][C:26]=2[CH:38]([CH3:40])[CH3:39])=[O:24])[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:28]([CH:36]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:27][C:26]=2[CH:38]([CH3:40])[CH3:39])=[O:24])[CH2:15][CH2:14]1
Reactant: CC(C)c1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCCN1CCN(C)CC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCCN1CCN(C)CC1
Yield: 44 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (53 mg, 0.25 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid [3-(4-methylpiperazin-1-yl)propyl]amide (300 mg) to give 65 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
450 g (3 mol) of 4-methylphenyl-acetic acid (Aldrich), 1.13 l (12 mol) of tert-butanol and 90 g (0.74 mol) of 4(N,N dimethylamino)pyridine are dissolved in 2 l of dichloromethane. After addition of 680 g (3.3 mol of dicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, the mixture is stirred at 25° C. for 20 h, the precipitated urea is filtered off with suction and washed with 200 ml of dichioromethane, and the organic phase is washed twice each with 500 ml of 2 M hydrochloric acid and water. The organic phase is concentrated and distilled.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][SH:7])[NH2:5].[CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[C:15]([OH:17])=[O:16])=O>O1CCCC1.C(Cl)(Cl)Cl>[C:15]([CH:14]([N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23])[CH2:13][CH2:12][CH2:11][CH:9]1[NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:8])[CH2:6][S:7]1)([OH:17])=[O:16]
Reactant: O=CCCC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: COC(=O)[C@@H](N)CS
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CSC(CCCC(C(=O)O)N2C(=O)c3ccccc3C2=O)N1

Procedure:
A solution of L-cysteine methyl ester (1.71 g) and 5-formyl-2(S)-phthalimidopentanoic acid (3.49 g) in 120 ml of tetrahydrofuran was stirred under nitrogen for 2.5 hours and then taken to dryness to yield a white foam. This residue was dissolved in 250 ml of chloroform and washed with water (2×30 ml). The combined aqueous layers were back extracted with chloroform (2×30 ml). The organic layers were dried (Na2SO4) and then concentrated in vacuo to give a white foam, 4.83 g. Tlc on silica [4:1 Ethyl acetate:acetic acid] indicated a major spot at Rf =0.72. Exact mass measurement showed a molecular ion at 392.1024 (calcd. 392.1041). 'H NMR spectrum (CDCl3) showed a multiplet at δ7.72 (4H) and a singlet at δ3.78(3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19].Cl.[NH:35]1[CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[N:35]1([C:14]([C:13]2[CH:17]=[CH:18][C:10]([O:9][C:8]3[CH:20]=[C:21]([C:23]4[NH:24][C:25]([C:28]5[S:29][CH:30]=[CH:31][N:32]=5)=[CH:26][CH:27]=4)[CH:22]=[C:6]([O:5][C@@H:4]([CH3:33])[CH2:3][O:2][CH3:1])[CH:7]=3)=[C:11]([CH3:19])[CH:12]=2)=[O:16])[CH2:38][CH2:37][CH2:36]1
Reactant: C1CNC1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzoic acid (58 mg, 0.125 mmol) synthesized in Example (53a) and azetidine hydrochloride (29 mg, 0.310 mmol) were dissolved in dichloromethane (10.0 mL), and HATU (95 mg, 0.250 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.861 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=75%-90%) to afford the desired compound (58 mg, yield 92%) as a yellow solid.
Reaction SMILES: COC1C=CC([C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24]C3C=CC4C(=CC=CC=4)N=3)=[CH:19][CH:18]=2)=CC=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:14][C:13]1([CH3:15])[O:12][C:11](=[O:16])[C:10]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:36]3[CH:37]=[CH:38][C:39]4[C:40](=[CH:13][CH:9]=[CH:10][CH:11]=4)[N:35]=3)=[CH:21][CH:22]=2)=[C:9]1[C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2(C)C)cc1
Product: CC1(C)OC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1c1ccncc1
Yield: 76 %

Procedure:
Following the procedure for the preparation of 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one (Example 33) using pyridine-4-yl boronic acid provided the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([NH2:13])[N:3]=1.[CH3:14][C@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([CH3:24])=[CH:20][CH:21]=2)[C@@H:16]1[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:7]1[C:2]([NH:25][C@H:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([CH3:24])[CH:18]=3)[CH2:23][C@@H:15]2[CH3:14])=[N:3][C:4]([NH2:13])=[N:5][C:6]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Reactant: Nc1nc(Cl)c(Cl)c(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc2c(c1)[C@H](Nc1nc(N)nc(C(F)(F)F)c1Cl)[C@@H](C)C2
Temperature: 125 °C
Yield: 58 %

Procedure:
A mixture of 0.10 g (0.43 mmol) of 4,5-dichloro-6-(trifluoromethyl)pyrimidin-2-amine, 0.08 g (0.51 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine and 0.14 g (1.3 mmol) of potassium carbonate in 1 ml of dimethylacetamide as solvent is heated at 125° C. for 30 minutes in a microwave appliance (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture is absorbed on silica gel and, following column chromatographic separation, 0.089 g of 5-chloro-N4-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-6-(trifluoromethyl)pyrimidin-2,4-diamine is obtained (solid, 55% yield, 95% purity).
Reaction SMILES: [CH2:1]([C:3]([CH2:19][CH3:20])([C:16]([O-:18])=[O:17])[C:4]([O:6]C(C)CCCCCCC)=[O:5])C.[OH-].[K+].[CH2:23](O)[CH3:24]>O>[CH3:1][C:3]([CH2:19][CH2:20][CH2:1][CH2:3][CH2:19][CH2:20][CH2:23][CH3:24])([C:16]([OH:18])=[O:17])[C:4]([OH:6])=[O:5]
Reactant: CCO
Reactant: CCCCCCCC(C)OC(=O)C(CC)(CC)C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCC(C)(C(=O)O)C(=O)O

Procedure:
To a stirring mixture of methyloctyl diethylmalonate (6.8 g, 25 mmol) in water (50 mL) and ethanol (50 mL) was added KOH pellets (15.0 g, 250 mmol). The cloudy mixture was then refluxed overnight where it became clear. The solvent was concentrated in vacuo to a white solid. The solid was dissolved in water and extracted with ether (2×). The water layer was then acidified with concentrated HCl and a solid precipitated out of solution. The white solid was filtered and the resulting mother liquor was extracted with ether in order to isolate any additional product. The combined organic layers were concentrated in vacuo and the resulting white solid was added to the filtered solid and dried in a vacuum oven. This afforded 4.3 g of pure product (75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:40]([S:42]([NH2:45])(=[O:44])=[O:43])[CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:45][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc5ccccc5c4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc5ccccc5c4)CC3)cnc12
Yield: 60.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-[4-(2-naphthyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (69 mg, 0.13 mmol) obtained in step 2 and ethanesulfonamide (68 mg, 0.65 mmol), the title compound (48 mg, 60%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:28](=[O:38])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[OH:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][NH:29][C:28]([C:19]1[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[C:3]([OH:39])=[O:2])=[O:16])=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)=[O:38]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-{[5-(3-Hydroxy-benzylcarbamoyl)-3-phenyl-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (40 mg, 0.07 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (30 mg, 0.71 mmol) in water (3 mL). The mixture was then stirred at room temperature 4 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 20.9 mg (68%). MS m/e 549.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.C([Li])CCC.[F:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[C:29](N(OC)C)=[O:30]>C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH3:19])[CH:6]=[CH:5]3)=[O:30])[CH:35]=[CH:36][CH:37]=1
Reactant: CON(C)C(=O)c1cccc(F)c1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc2cc(C(=O)c3cccc(F)c3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (320 mg, 1.0 mmol) in THF (10 mL) was treated with 2.5M n-butyllithium (0.5 mL, 1.25 mmol) at −78° C. The solution was mixed for 15 min, and treated with a solution of 3-fluoro-N-methoxy-N-methylbenzamide (2.0 mmol) in THF (5.0 mL) at −78° C. The mixture was allowed to warm to room temperature overnight, quenched by 1 mL ethanol, concentrated, and diluted with ethyl acetate. The mixture was washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with HCl in IPA:ethyl acetate to give the dihydrochloride salt. mp 162-164° C.(dec.); MS (ESI) 363 (M+H)+; 1H NMR (DMSO-d6) δ 8.79 (1H, d), 8.53 (1H, d), 8.30 (1H, d), 8.21(1H, dd), 7.82 (1H, d), 7.6 (4H, m), 3.9 (1H, br, m), 3.63 (2H, br, m), 3.50 (2H, br, m), 3.21 (1H, br, m), 2.2 (1H, m), 1.98 (2H, br, m), 1.7 (1H, br, m), 1.46 (1H, m), 1.30 (3H, d).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:11]([O:10][C:8]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCBr
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a stirred suspension of 3-bromopropylamine hydrobromide (2 g, 9.14 mM) in 40 mL dry THF was added, via hypodermic syringe, benzyl chloroformate (1.64 g, 9.60 mM) at room temperature. After cooling to 0° C., diisopropylethylamine (1.6 mL, 9.20 mM) was added dropwise via syringe and the reaction mixture was allowed to stir at 0° C. for 1 hour. The crude reaction mixture was filtered over a pad of Celite and solvents were evaporated. The residue was flash chromatographed on silica gel, eluting with 10-20-30% EtOAc/hexane to afford 1.56 g desired product as a liquid, homogeneous by TLC in 80:20 hexane-EtOAc;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][C:14]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:13]=3[NH:12][C:11](=[O:24])[CH:10]2[CH2:25][CH:26]=[CH2:27])=[CH:5][CH:4]=1>C(O)(=O)C.FC(F)(F)C(O)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][C:14]3[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=3[NH:12][C:11](=[O:24])[CH:10]2[CH2:25][CH2:26][CH3:27])=[CH:5][CH:4]=1
Reactant: C=CCC1C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccc(OC)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCCC1C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccc(OC)cc1
Reaction time: 4 h
Yield: 100.4 %

Procedure:
1,3,4,5-Tetrahydro-4-(4-methoxyphenyl)-3-(2-propenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one (3.50 g; 9.32 mmole; see Example 5, Method II, part D) was dissolved in glacial acetic acid (100 ml) and trifluoroacetic acid (50 ml). Palladium on charcoal (0.71 g) was added to the degassed solution, and the mixture was placed on a Parr apparatus for four hours. The solution was then filtered through a pad of Celite and the Celite was rinsed several times with ethyl acetate. The concentrated mixture was vacuum dried yielding 3.53 g of the title compound as a solid.