Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[CH:34][C:33]=1[S:40](Cl)(=[O:42])=[O:41].CO>C(#N)C.ClCCl>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[CH:34][C:33]=1[S:40]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NS(=O)(=O)c3cc(Cl)c(Cl)cc3Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) and sodium hydrogen carbonate (0.05 g; 0.6 mmole) were mixed in acetonitrile (10 ml) and stirred at room temperature for 15 minutes. The mixture was then cooled in an ice-bath and 2,4,5-trichlorobenzenesulfonyl chloride (0.184 g; 0.657 mmole) was added. After addition, the ice-bath was removed and the reaction mixture was heated to reflux for 4 hours and then evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane and then methanol (2%) in dichloromethane as eluant gave 0.28 g (89% yield) of 3-(4-{2-[4-(2,4,5-trichlorobenzenesulfonylamino)phenyl]ethoxy}phenyl]-(S)-2-ethoxypropanoic acid.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(NC(C(O)=O)C(C)C)(=O)C1C=CC=CC=1.Cl.ClC1C=CC(C2CCNCC2)=CC=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:27][CH2:28][N:29]([C:16](=[O:18])[CH:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:13]([CH3:14])[CH3:15])[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
Example 213 was prepared in a similar manner as described for the preparation of Example 208 with the exceptions that Cbz-DL-valine and 4-(4-chlorophenyl)-4-hydroxypiperidine were substituted for benzoyl-DL-valine and 4-(4-chlorophenyl)piperidine hydrochloride, respectively. MS found: (M+H)+=446.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]2[N:29]([CH2:37][CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][C:33]([CH3:35])([CH3:34])[C:27]=2[CH:26]=1.Cl>O1CCOCC1.COCCO>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[CH:40]=[CH:39][C:28]3[N:29]([CH2:37][CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][C:33]([CH3:34])([CH3:35])[C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)ccc21
Yield: 92.3 %

Procedure:
Combined (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (113 mg, 0.3185 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (74 mg, 0.3185 mmol), 4 N HCl in dioxane (100 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 3 hours. Evaporated off solvent and purified with normal phase chromatography to yield a yellow solid, 7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (162 mg, 92%). LCMS: m/z=551.00 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.21 (d, 1H, J=9.4 Hz), 8.04 (s, 1H), 7.69 (d, 1H, J=9.4 Hz), 7.60 (s, 1H), 7.34 (s, 1H), 7.19 (d, 1H, J=8.1 Hz), 6.92 (s, 1H), 6.56 (s, 1H), 6.49 (d, 1H, J=8.6 Hz), 3.94 (s, 3H), 3.90 (m, 4H), 3.82 (m, 2H), 3.16 (m, 4H), 2.32 (m, 2H), 2.06 (m, 2H), 1.33 (m, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:23][CH2:24][CH:25]=[CH2:26])([C:18]([O:20]CC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CC(O)=O>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:23][CH2:24][CH:25]=[CH2:26])[C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCCC(NC(=O)OCc1ccccc1)(C(=O)O)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of diethyl 2-(benzyloxycarbonylamino)-2-(but-3-enyl)malonate (4.8 g, 13.23 mmol) in ethanol (45 mL) was cooled to −30° C. and treated with an aqueous solution of potassium hydroxide (1.55 g, 27.76 mmol in 15 mL water). After the addition was complete, the solution was warmed to 0° C. for 30 minutes followed by room temperature for 1 h. With the reaction complete, the mixture was acidified with AcOH (1.8 g) and extracted with ethyl acetate (1×50 mL). The aqueous layer was acidified to pH 3 with 3 N hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1×50 mL), dried over MgSO4 and concentrated to give 2-(benzyloxycarbonylamino)-2-(ethoxycarbonyl)hex-5-enoic acid (3.0 g, 68%). 1H NMR (CDCl3) δ 10.00 (bs, 1H), 7.37 (m, 5H), 7.26-6.93 (m, 1H), 6.21 (bs, 1H), 5.76 (m, 1H), 5.94-5.22 (m, 4H), 4.27 (m, 2H) 2.43 (m, 2H), 1.96-1.93 (m, 2H), 1.27-1.21 (m, 3H). MS found for C17H21NO6 m/z [336 (M+1)].
Reaction SMILES: O1CCCC1.[O:6]([C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[N:21][OH:22])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[O:6]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[O:22][N:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1cccc(Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2cccc(Oc3ccccc3)c2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
To a tetrahydrofuran (10.0 mL) solution of (3-phenoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.573 mmol) described in Manufacturing Example 64-1-3 and 3-ethynyl-pyridin-2-ylamine (30.0 mg, 0.254 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (106 μL, 0.762 mmol) at room temperature, which was stirred for 2 hours at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2), the mixture was further purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound (6.6 mg, 43%) as a trifluoracetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](#[N:14])[CH:12]=[CH2:13].[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]2[O:10][CH2:13][CH:12]([C:11]#[N:14])[CH:5]([OH:6])[C:4]=2[CH:3]=1
Reactant: C=CC#N
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC1COc2ccc(Cl)cc2C1O
Reaction time: 8 h

Procedure:
To a stirred, refluxing mixture of 50 g of 3-chloro-6-hydroxybenzaldehyde and 62 ml of acrylonitrile in 50 ml of water was added dropwise over a three-hour period a solution of 12.8 g of sodium hydroxide in 120 ml of water. Then an additional 62 ml of acrylonitrile was added and the stirred mixture was refluxed for 2 hours, then allowed to stand at room temperature overnight. The crystals which formed were filtered off, washed with water and dried to give a solid, which was dissolved in ethanol. The solution was cooled and filtered to give 6-chloro-3,4-dihydro-4-hydroxy-(2H)- 1-benzopyran-3-carbonitrile (5A), a solid. A mixture of 5A with 250 ml of methanol containing 2 ml of sulfuric acid, was refluxed for 4 days and stripped of solvent. The resulting residue was dry column chromatographed over silica gel, using Solvent No. 3 as eluent. The product obtained on workup was recrystallized from ether to give methyl 6-chloro-2H-1-benzopyran-3-carboxylate (5B), as light yellow needles, m.p.: 106°-109°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:49][CH2:50][CH:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:46][CH2:47]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCC1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-(2-methanesulfonyl-ethyl)-piperidine hydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C37H47N4O4SCl2 [(M+H)+] 713.2690, observed 713.2689.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:23][CH2:24][CH2:25][Cl:26])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-benzyloxyphenol (2 g), potassium carbonate (6.90 g) and 1-bromo-3-chloropropane (4.94 mL) in N,N-dimethylformamide (10 mL) affords 2.07 g of O-benzyl-4-(3-chloropropoxy)phenol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([Cl:1])=[N:3]2)=[CH:13][CH:14]=1
Reactant: Clc1n[nH]c2ccccc12
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nc(Cl)c3ccccc32)cc1
Yield: 86.9 %

Procedure:
Using the general procedure, 3-chloroindazole (0.153 g, 1.00 mmol) was coupled with 4-bromotoluene, (148 μL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (32 μL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 50:1) provided 0.211 g (87% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.52 (m, 2H), 7.43 (m, 1H), 7.24 (d, J=8.2 Hz, 2H), 7.22 (m, 1H), 2.38 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15](O)[CH3:16])(C)(C)C.O.Cl.[S-:21][C:22]#[N:23].[K+]>C(O)C>[Cl:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][C:22](=[S:21])[NH:23][CH:15]2[CH3:16]
Reactant: N#C[S-]
Reactant: CC(O)c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1NC(=S)Nc2ccc(Cl)cc21
Yield: 84.5 %

Procedure:
[4-Chloro-2-(1-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester (525 mg, 1.93 mmol) was suspended in a mixture of ethanol (1.5 ml), water (2.3 ml) and aqueous concentrated hydrogen chloride solution (0.6 ml). Potassium thiocyanate (206 mg, 2.1 mmol) was added and the reaction was heated to reflux for 3 hours. The product precipitated from the reaction and was filtered off after cooling, washed with water and ethanol and dried in vacuo to give the title compound (347 mg, 84%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][O:6][CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: OCc1cccc(Br)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOCc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
To a tetrahydrofuran (100 mL) solution of 3-bromobenzyl alcohol (10 g, 54 mmol) was added sodium hydride (2.3 g, 98 mmol, 60% in oil) at room temperature. Then, chloromethyl methyl ether (5.2 g, 64 mmol) was added to this suspension, which was stirred for 15 minutes at 60° C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1) to obtain the title compound (10 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[C:15]3[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=2)=[N:5][N:6]=1>CO>[CH3:1][C:2]1[S:3][C:4]([C:7]2[C:15]3[C:14]([C:16]4[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=4)[NH2:22])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:8]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(-c2cn(COCC[Si](C)(C)C)c3ncnc(-c4cccc([N+](=O)[O-])c4)c23)s1
Solvent: CO
Product: Cc1nnc(-c2cn(COCC[Si](C)(C)C)c3ncnc(-c4cccc(N)c4)c23)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methyl-5-(4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3,4-thiadiazole (0.38 g, 0.81 mmol) in methanol (10 mL) was added Pt (1% on C, V doped) (343 mg). The atmosphere was purged with hydrogen and the solution was stirred for 4 hours at room temperature under hydrogen atmosphere (1 atm). The reaction was then filtered and concentrated in vacuo to afford crude 3-(5-(5-methyl-1,3,4-thiadiazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline as a dark green solid. LRMS (ESI) calc'd for C21H27N6O3SSi [M+H]+: 439, found 439.
Reaction SMILES: [C:1]1(=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CCO>[C:1]1(=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Temperature: 87.5 °C
Yield: 52 %

Procedure:
To a solution of methyl 4-[cyclohexylidene(4-hydroxyphenyl)methyl]benzoate (156) (0.175 g, 0.54 mmoL) in THF (3 mL) and EtOH (3 mL) was added 1 N NaOH (6 mL) at RT. The reaction mixture was heated between 85-90° C. under a nitrogen atmosphere for 2 h. The oil bath was removed and the reaction mixture was allowed to cool to RT. The reaction mixture was partially concentrated in vacuo to remove the THF and EtOH. The basic aqueous mixture was diluted with H2O and the pH was adjusted to ˜1 (as judged by litmus paper) with 1 N HCl. The acidic aqueous mixture was extracted with CH2Cl2 (2×). The organic extracts were combined, dried (MgSO4), filtered, and the filtrate was concentrated to give the 0.087 g (52%) of compound 157 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (m, 6H), 2.11 (m, 2H), 2.17 (m, 2H), 6.67 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 9.35 (s, 1H), 12.81 (br s, 1). LRMS (ESI): m/z 307 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][CH2:37][NH2:38]>>[CH2:15]([N:14]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:38][CH2:37][CH2:36][C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:16]
Reactant: NCCc1cccs1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3cccs3)n2)c1)C1CCNCC1

Procedure:
Intermediate 84 was coupled with 2-thiophen-2-yl-ethylamine following procedure F. The product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 422.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][C@@H:11]([N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[CH:23]1)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][N:22]([C@@H:11]([C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:39])=[O:8])[CH:23]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 1.83 h
Yield: 74.9 %

Procedure:
According to the procedure described in Example 1(a), a mixture of 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester (137 mg, 0.26 mmol) in EtOH (2.5 mL) and EtOAc (2.5 mL) was hydrogenolyzed after 110 minutes to give a white solid, which was triturated with CH2Cl2/hex to provide 85 mg (75%) of 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid as a white solid, mp 150-2° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=S)[CH:16]([CH3:18])[CH3:17].[C:20]([NH:28][NH2:29])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)CCC>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[N:14]1[C:15]([CH:16]([CH3:18])[CH3:17])=[N:29][N:28]=[C:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)C(=S)Nc1ccc2c(c1)Cc1ccccc1-2
Solvent: CCCCO
Product: CC(C)c1nnc(-c2ccccc2)n1-c1ccc2c(c1)Cc1ccccc1-2
Temperature: 130 °C
Yield: 7.4 %

Procedure:
In a 200 mL three-neck flask were put 13 g (50 mmol) of N-(9H-fluoren-2-yl)isobutyrthioamide, 8.2 g (60 mmol) of benzoylhydrazine, and 70 mL of 1-butanol, and the mixture was heated and refluxed at 130° C. for 10 hours. After that, the solid in the reaction mixture was removed by suction filtration. The resulting filtrate was concentrated to precipitate a solid. After that, 1-buthanol was distilled off to precipitate a solid. The precipitated solid was removed by suction filtration, and the filtrate was purified by silica gel column chromatography. A mixed solvent of ethyl acetate and toluene (ethyl acetate: toluene=1:1) was used as a developing solvent. The resulting fraction was concentrated to give a solid. The obtained solid was recrystallized from ethyl acetate to give 1.3 g of a white solid of 4-(9H-fluoren-2-yl)-5-isopropyl-3-phenyl-4H-1,2,4-triazole in a yield of 7%. The synthesis scheme of Step 3 is shown in (c-3) below.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[N:34]([CH2:35][CH3:36])[CH2:32][CH3:33]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(NCc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI/CI): predicted mass C25H28N6O2, 444.2.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>C(OCC)C>[NH2:1][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: N
Reactant: Fc1cc(OC(F)(F)F)nc(F)n1
Solvent: CCOCC
Product: Nc1nc(F)cc(OC(F)(F)F)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
8.7 g (0.51 mol) of gaseous ammonia were passed over the course of 1 hour into a stirred mixture of 51 g (0.255 mol) of 2,4-difluoro-6-trifluoromethoxypyrimidine and 200 ml of diethyl ether at −75 to −70° C. The mixture was stirred at −70° C. for 1½ hours and at room temperature for 1 hour and then concentrated under reduced pressure. The residue was taken up in methylene chloride and the organic phase was extracted with water, dried, concentrated and chromatographed on silica gel with 8:1 petroleum ether/ether, resulting in 38.1 g (75.6% of theory) of the title compound as colorless crystals of melting point 86-89° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=12.C(OC(=O)C)(=[O:21])C>>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][NH:15][C:14](=[O:21])[CH:13]=3)[CH:7]=[CH:6][C:5]=12
Reactant: [O-][n+]1ccc(OCc2ccc3nccn3c2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2ccc3nccn3c2)cc[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine 1-oxide (1.69 g, 7.04 mmol) was heated at 140° C. in acetic anhydride (20 mL) for 4 h. The mixture was concentrated and heated at 80° C. for 3 h in a mixture of 1:1 MeOH/H2O (50 mL). The resulting solution was concentrated. The residue was partially dissolved in iPrOH (75 mL). Et2O (200 mL) was added, and the mixture was allowed to sit at ambient temperature for 1 h. The resulting solids were collected by filtration, washed with Et2O and dried under reduced pressure. The solids were again subjected to iPrOH and Et2O, and the solids were removed by filtration. The filtrate was concentrated to afford the title compound (0.47 g, 28%) as a dark brown solid: 1H NMR (300 MHz, CD3OD) δ 8.60 (d, J=0.7 Hz, 1H), 7.87 (d, J=0.6 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.57 (s, 1H), 7.40-7.27 (m, 2H), 6.18 (dd, J=7.3, 2.5 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.13 (s, 2H).