Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])=[N:11][C:12](=[O:22])[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[Li+].[OH-].O>O1CCCC1>[CH2:15]([O:14][C:13]1[C:12](=[O:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[NH:9][C:8]=1[C:6]([OH:7])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
5-(Benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid tert-butyl ester (67) (2.69 g, 5.71 mmol, Eq: 1.00) and LiOH (683 mg, 28.5 mmol, Eq: 5) were stirred in tetrahydrofuran (18 ml)/water (9.00 ml) under reflux for 6 h, at room temperature overnight and again to reflux for 3 h. Then the solvent was mostly removed. The remaining oil was diluted with water and extracted with ethyl acetate. The aqueous layer was cooled in an ice bath and was acidified with HCl conc. Precipitate formed, was collected by filtration, washed with water and dried to afford 5-(benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (68) (2.14 g, 5.15 mmol, 90.3% yield) as a white solid.
Reaction SMILES: CC[C@H:3]1[C@@H:16]([OH:17])[C@@H:15]2[C@H:10]([CH2:11][CH2:12][C@:13]3([CH3:28])[C@@H:20]([C@@H:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:19][CH2:18][C@H:14]32)[C@:9]2([CH3:29])[C@H:4]1[CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2.O[C@@H:32]1CC[C@@]2(C)[C@H](CC(=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(O)=O)C1.OS(O)(=O)=O>CO>[CH3:32][O:27][C:25](=[O:26])[CH2:24][CH2:23][C@H:21]([C@@H:20]1[C@:13]2([CH3:28])[C@H:14]([C@H:15]3[C@H:10]([CH2:11][CH2:12]2)[C@:9]2([CH3:29])[C@@H:4]([CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2)[CH2:3][C:16]3=[O:17])[CH2:18][CH2:19]1)[CH3:22]
Reactant: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The present invention relates to a process for preparing obeticholic acid Form 1, comprising the steps of reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with CH3OH and H2SO4 to form 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester; reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester with Li[N(CH(CH3)2)2] and Si(CH3)3Cl to form 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester; reacting 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester with CH3CHO to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester; reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid; reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid; reacting 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH4 to form crystalline obeticholic acid, and converting crystalline obeticholic acid to obeticholic acid Form 1.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([C:6]([Br:14])=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:15].[Cl:16][C:17]1[C:18]([N:23]2[C:27]([C:28](O)=O)=[CH:26][C:25]([O:31][CH3:32])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Br:14][C:6]1[C:5]2=[CH:4][C:3]([Cl:15])=[C:2]3[C:10]([C:11](=[O:13])[O:12][C:28]([C:27]4[N:23]([C:18]5[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=5)[N:24]=[C:25]([O:31][CH3:32])[CH:26]=4)=[N:1]3)=[C:9]2[NH:8][N:7]=1
Reactant: Nc1c(Cl)cc2c(Br)n[nH]c2c1C(=O)O
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 0 °C
Yield: 34.1 %

Procedure:
To a suspension of 400 mg (1.38 mmol) of 6-amino-3-bromo-5-chloro-1H-indazole-7-carboxylic acid in 16 mL of anhydrous tetrahydrofuran at 10° C., is added 349 mg (1.38 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid followed by 499 μL (6.20 mmol) of pyridine. Then the suspension is cooled to 0° C. and 376 μL (4.82 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature over the night. The reaction is not complete and therefore 166 μL (2.07 mmol) of pyridine are added followed by 349 mg (1.38 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid. The reaction is stirred again at ambient temperature for 5 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained is purified by flash chromatography (SiO2, heptane/ethyl acetate 1:1) affords 200 mg (0.47 mmol, 34%) of the product as a solid; LC/MS:509/511 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Br)[CH3:23]>CC(=O)CC>[CH2:22]([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:8]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:14][CH:13]=1)[CH3:23]
Reactant: Oc1ccc(C=Cc2ccncc2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1ccc(C=Cc2ccncc2)cc1

Procedure:
One heats a mixture of 30 g (0.15 mol) 4-[2-(4-pyridinyl)-ethenyl]-phenol, 21 g potassium carbonate, 750 ml butanone and 33 ml (0.23 mol) 4-bromobutyric acid ethyl ester to reflux for 24 h, filters, evaporates the filtrate, mixes with water, extracts with dichloromethane, dries the extract, evaporates the triturates the residue with ether. There remain 42.3 g of title compound (89% of theory) of the m.p. 83°-85° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[N:14]=[CH:15][C:8]=12>>[Cl:3][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[N:14]=[CH:15][C:8]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccc(C#N)c1-n1ncc2c(O)ncnc21
Product: N#Cc1cccc(C#N)c1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
Phosphoryl trichloride (6842 μl, 71.40 mmol) was added to 2-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)isophthalonitrile (Intermediate BK2) (1872 mg, 7.14 mmol). The resulting solution was stirred at 100° C. for 4 hours. The reaction mixture was evaporated and ice/water added to the residue. After stirring for 1 hour a precipitate formed that was filtered off and washed with water (3×5 mL) to give a yellow solid. This was dried under high vacuum for 20 hours to give the product (879 mg, 43.9%) which was used without further purification.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:9][Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:19]([Sn:10]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][O:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COC1CCC1
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a solution of 2.3 g of cyclobutanol in 60 mL of dry THF was added 624 mg of 98% sodium hydride. After stirring 2 h, 5.6 g of iodomethyl tributyltin (prepared as described by Seitz et al 1983 Synthetic Comm. 13 129) was added and the reaction mixture was stirred at room temperature for 48 h, and then poured onto water and extracted with hexanes. The extracts were washed with brine, dried and evaporated to a crude product that was purified by flash chromatography (hexanes then 67% ethyl acetate/hexanes eluents) to afford 1.64 g of tributyl (cyclobutyloxymethyl)tin as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Mg].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[O:25]>CCOCC.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2([OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A solution of 25 g of 1-bromo-2-trifluoromethoxybenzene in 130 ml of ether is added drop wise to a mixture of 2.8 g of magnesium in 20 ml of ether, and once the refluxing has started it is maintained. At the end of the addition the mixture is refluxed for 1 hour. A mixture of 7.5 g of 5-chloro-1H-indole-2,3-dione in 100 ml of THF is then added, at a temperature below 40° C., followed by refluxing for 1 hour. After cooling to RT, the reaction mixture is poured into an ice/concentrated HCl mixture, the resulting mixture is extracted with EtOAc, the organic phase is washed with water, with IN NaOH solution and dried over Na2SO4, and the solvent is evaporated under vacuum. 6.5 g of the expected product are obtained after crystallization from a DCM/iso-ether mixture (20/80; v/v); m.p.=214° C.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].O.[OH-].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=O)=[CH:21][CH:20]=1>CO>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=[N:6][OH:7])=[CH:21][CH:20]=1
Reactant: NO
Reactant: O=CCc1ccc(COc2ccccn2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: ON=CCc1ccc(COc2ccccn2)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of hydroxylamine sulfate (19.7 g) and water (250 mL) was added 1N aqueous sodium hydroxide (240 mL) at 0° C., which was stirred at the same temperature for 15 minutes. To the reaction mixture was then added dropwise a mixture of 4-(pyridin-2-yloxymethyl)-phenyl-acetaldehyde described in Manufacturing Example 2-3-3 (27.3 g) and methanol (250 mL), which was stirred overnight at room temperature. The precipitated solids were filtered to obtain the title compound (20.3 g) as an E/Z mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:22]([CH3:33])([C:28]([O:30]CC)=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24].[OH-].[K+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH3:33])[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)C(=O)O
Yield: 70.6 %

Procedure:
To a solution of the compound of Example 38 (16.8 g) in ethanol (167 mL) was added potassium hydroxide (2.40 g), and the resultant solution was stirred at 50° C. for 24 hours. To the reaction solution was added water, neutralized with 2 mol/L aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturatedbrine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane ethyl acetate=1:1) to obtain the target product (11.2 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][C:14]([CH:16]=[N:19][OH:20])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc(C=O)o2)cc1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccc(C=NO)o2)cc1OC

Procedure:
5-(3,4-Dimethoxyphenyl)furaldehyde (100 g, 0.43 mole), hydroxylamine hydrochloride (59.9 g, 0.86 mole) and anhydrous sodium acetate (70.69 g) was treated with solution of water (150 ml) in SDA #32 (2200 ml). The reaction mixture was heated at reflux for 6 hours. The mixture was filtered hot and the filtrate chilled. The intermediate was collected and used without further purification in Part B; 38 g (36%), m.p. 148°.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1>>[CH2:1]([NH:8][C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3ccccc3)nnnc12

Procedure:
Compound 6 was prepared following general synthetic scheme 7 wherein benzylamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [280 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.42 (s, 1H), 9.31 (t, 1H), 8.53 (t, 1H), 8.04 (s, 1H), 7.98 (t, 1H), 7.41 (d, 2H), 7.34 (t, 2H), 7.28-7.24 (m, 1H), 4.92 (d, 2H).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:25][C:26](=[CH2:28])[CH3:27])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].CCN(CC)CC>CCOC(C)=O.[Pd]>[CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:25][CH:26]([CH3:27])[CH3:28])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:20])[F:22])[CH3:2]
Reactant: C=C(C)CN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC(C)C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-methallyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.010 g, 0.025 mmol in 1.5 mL EtOAc and 0.1 mL Et3N was added 10% Pd on carbon (0.006 g) and the mixture was vigorously stirred under H2 atmosphere for 1 h. The reaction mixture was filtered through Celite and concentrated to afford 0.010 g (100% yield) of (R)-3-ethyl-3,4-dihydro-4-isobutyl-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. This material (0.010 g, 0.025 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (0.5 mL) in AcOH (1.0 mL) and heated at 95° C. to afford Compound 115 (0.008 g, 89% yield) as a yellow solid. Rf 0.5 (9:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 11.81 (broad s, 1H), 7.11 (s, 1H), 7.00 (d, 1H, J=9.0), 6.92 (d, 1H, J=9.0), 4.33 (dd, ABX, 1H, J=10.4, 1.2), 3.98 (dd, ABX, 1H, J=10.4, 2.3), 3.23 (dd, ABX, 1H, J=14.5, 4.8), 3.15–3.10 (m, 1H), 2.80 (dd, ABX, 1H, J=14.5, 9.8), 2.07–1.97 (m, 1H), 1.62–1.49 (m, 2H), 1.01 (d, 3H, J=6.5), 0.98–0.92 (m, 6H).
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].[C:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[C:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:6]3[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]4[S:12][CH:13]=[C:14]([C:16]5[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=5)[N:15]=4)=[CH:8][CH:7]=3)=[CH:25][CH:26]=2)=[O:32])[CH2:38][CH2:37]1)(=[O:35])[CH3:34]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CC(=O)N1CCC(N)CC1
Product: CC(=O)N1CCC(NC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)CC1
Yield: 4 %

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 1-acetylpiperidin-4-amine (available from Aldrich Chemical Company, Inc.; 88 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4′-(1-acetyl-piperidin-4-ylcarbamoyl)-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (5 mg, 4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br s, 1H), 8.45 (s, 1H), 8.33 (s, 3H), 8.19 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 4.35 (d, J=12.3 Hz, 1H), 4.05 (br s, 1H), 3.85 (d, J=13.3 Hz, 1H), 3.16 (t, J=11.8 Hz, 1H), 2.69 (d, J=13.3 Hz, 1H), 2.02 (s, 3H), 1.78-1.93 (m, 1H), 1.18-1.58 (m, 4H).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)(=O)=O.[C-:23]#[N:24].[Na+].CS(C)=O>O>[C:23]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)#[N:24]
Reactant: [C-]#N
Reactant: CCCCCOc1ccc(-c2cnc(S(C)(=O)=O)nc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCOc1ccc(-c2cnc(C#N)nc2)cc1
Yield: 43.6 %

Procedure:
This compound (XI) (1.8 g, 0.006 mol) and NaCN (0.275 g, 0.006 mol) were added to dimethylsulfoxide (5 ml), followed by mixing at 100° C. for one hour, allowing the resulting material to cool, adding water (15 ml), filtering off the resulting crystals and recrystallizing crystals from ethanol to obtain 2-cyano-5-(4-pentyloxyphenyl)pyrimidine (XII) (0.7 g) (yield: 47%) having a melting point of 100° C.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[OH:30])=[O:22]>>[CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[OH:30])=[O:22])[CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Reactant: O=C(CCCCl)c1ccc(F)cc1O
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCO3)c1ccc(F)cc1O

Procedure:
The title compound was prepared by the method of Example 361 as a yellow oil (8 mg, 17%) from (±)-cis-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (30 mg, 0.12 mmol) and 4-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-butanone (52 mg, 0.24 mmol). 1H NMR (CDCl3, 300 MHz) δ1.85-2.13 (m, 5H), 2.25-2.47 (m, 3H), 2.63-2.95 (m, 3H), 2.99 (t, J=7.0 Hz, 2H), 3.17-3.35 (m, 3H), 4.43 (dd, J=6.9, 2.2 Hz, 2H), 6.59-6.75 (m, 5H), 7.81 (dd, J=8.7, 6.6 Hz, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][Si:16]([CH3:18])([CH3:17])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-nitrophenol (5.0 g, 35.9 mmol) (Aldrich) in dimethylformamide (50 mL) was added imidazole (3.18 g, 46.7 mmol) (Aldrich) and t-butyldimethylsilyl chloride (6.49 g, 43.1 mmol) (Avocado Research Chemicals Ltd.). The reaction mixture was stirred at room temperature for 1 day. TLC analysis showed starting material was still present. Another portion of t-butyldimethylsilyl chloride (1.0 g, 6.63 mmol) was added and the mixture was stirred at room temperature for another 1 day. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with a mixture of water (100 mL) and aqueous 1N HCl (80 mL). The organic layer was then washed with water, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes (1:9, V/V) to afford 1-nitro-4-(1,1,2,2-tetramethyl-1-silapropoxy)benzene. (Yield 7.8 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20]>C1C=CC=CC=1>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][N:20]=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CN(C)CCCN
Solvent: c1ccccc1
Product: COc1cc(C=NCCCN(C)C)cc(OC)c1OC
Yield: 94 %

Procedure:
Interaction of 21 g of 3,4,5-trimethoxybenzaldehyde with 11 g of 3-dimethylaminopropylamine in 80 ml. of benzene following the procedure described in Example 1 yields 28.2 g of product as an oil, boiling point 162°-167° C. at 0.4-0.5 mm. of Hg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Br[C:27]1[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:36][N:35]([CH3:37])[C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)[CH:15]=[C:16]([O:18][C@H:19]3[CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[CH:17]=2)=[CH:32][N:31]=1)=[O:34]
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)nc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 23 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (206 mg, 0.6 mmol), 5-bromo-N,N-dimethyl-pyridine-2-carboxamide (CAS no. 845305-86-4) (165 mg, 0.72 mmol), cesium carbonate (587 mg, 1.8 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (112 mg, 0.12 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 160° C. for 6 hours. The N,N-dimethylacetamide was evaporated under reduced pressure and the residue was dissolved in water (20 mL) extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with 0-5% methanol in DCM. The resulting compound was dissolved in ethyl acetate (110 mL), washed with citric acid (1N, 10 mL), water (10 mL) and brine (10 mL), dried (MgSO4) and the solvent evaporated to afford the product (67 mg, 23%). 1H NMR δ (300 MHz, CDCl3) 2.14-2.26 (m, 1H), 2.52-2.67 (m, 1H), 2.55 (s, 3H), 2.94 (s, 3H), 3.15 (s, 6H), 3.34-3.57 (m, 2H), 4.94 (t, 1H), 6.97 (s, 1H), 7.23 (s, 1H), 7.40 (d, 1H), 7.46 (s, 1H), 7.72 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 8.58 (s, 1H), 9.52 (s, 1H); m/z 491 (M+H+).