Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([OH:14])=O)=[CH:2]1.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NOCC>O1CCCC1.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([NH:40][CH2:39][C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[O:36][CH3:35])=[O:14])=[CH:2]1
Reactant: COc1ccccc1CN
Reactant: O=C(O)C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCON=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirring solution of 3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid (179.8 g, 0.403 mole), 2-methoxybenzylamine (56.0 ml, 0.429 mole), and hydroxybenzotriazole hydrate (57.97 g, 0.429 mole) in anhydrous tetrahydrofuran (1.7 L) and anhydrous N,N-dimethylformamide (500 ml) under a nitrogen atmosphere at 0° C., were added triethylamine (60.0 ml, 0.430 mole) and 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride (82.25 g. 0.429 mole). The mixture was allowed to warm to room temperature under a nitrogen atmosphere for at least 20 hours. The mixture was concentrated on a rotary evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% citric acid solution (2×), saturated sodium bicarbonate solution (2×), and brine (2×) was performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness on a rotary evaporator. The title product was then filtered as a pink solid in two lots. Isolated 215.8 g (0.381 mole) of analytically pure material (95% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]3[CH2:31][CH2:30][CH2:29][CH:23]3[C:24](=O)[NH:25][C:26]=2[CH:27]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>COCCOC>[C:1]([O:5][C:6]([N:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]3[CH2:31][CH2:30][CH2:29][CH:23]3[C:24](=[S:41])[NH:25][C:26]=2[CH:27]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)Cc1ccc2c(c1)NC(=O)C1CCCC21
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)Cc1ccc2c(c1)NC(=S)C1CCCC21
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
A solution of 75 mg (0.17 mmol) of 7-(N-tert-butoxycarbonyl-3-chlorobenzyl-amino)methyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 5 ml of 1,2-dimethoxyethane is mixed with 138 mg (0.34 mmol) of Lawesson's reagent. After 1.5 hours at room temperature, the batch is refluxed for 0.75 hour and then concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 65 mg of product.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[N+:13]([O-:15])=[O:14])[CH:4]1[OH:24].CO.C([BH3-])#N.[Li+].[CH3:31][C:32]([CH3:34])=O>O>[ClH:1].[CH2:17]([O:16][C:8]1[C:9]([N+:13]([O-:15])=[O:14])=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]([OH:24])[CH:3]([NH:2][CH:32]([CH3:34])[CH3:31])[CH2:12][CH2:11]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1CCc2c(ccc(OCc3ccccc3)c2[N+](=O)[O-])C1O
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)NC1CCc2c(ccc(OCc3ccccc3)c2[N+](=O)[O-])C1O

Procedure:
To a solution of 5.0 g. of 2-amino-6-benzyloxy-1-hydroxy-5-nitro-1,2,3,4-tetrahydronaphthalene hydrochloride in 50 ml. of methanol are added 5.0 g. of lithium cyanoborohydride and 150 ml. of acetone, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is added in water and the resulting crystals are recovered by filtration, rinsed with water, dried and dissolved in alcoholic hydrochloric acid. After treatment with activated carbon, ethyl ether is added, whereupon 4.7 g. of 6-benzyloxy-2-isopropylamino-5-nitro-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride is obtained as colorless needles melting at 268°-270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[C:9]([F:12])([F:11])[F:10])[CH:7]=1.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].CCN(CC)CC>C(#N)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:6]=2[CH:7]=1
Reactant: COC(=O)CS
Reactant: O=C(c1cc(Cl)ccc1F)C(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2ccc(Cl)cc2c1C(F)(F)F

Procedure:
A solution of compound 67c (6.62 mmol, 1.5 g), methyl 2-mercaptoacetate 67d (6.62 mmol, 0.6 mL), and Et3N (8.6 mmol, 1.2 mL) in acetonitrile (12 mL) was heated at 75° C. for 4 h. The reaction was diluted with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to provide the compound 67e.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1Oc1ccc2ccccc2c1

Procedure:
A well stirred mixture of 37.2 g. (0.15 mole) of o-iodobenzoic acid, 21.6 g. (0.15 mole) of β-naphthol and 20.6 g. (0.15 mole) of potassium carbonate in 300 ml. of pyridine is heated at 50° C. for 1 hour. Cuprous chloride (5 g.) is added and the mixture is refluxed for about 18 hours. The mixture is poured in 1200 ml. of water and filtered. The filtrate is acidified and extracted with methylene chloride. The extracts are dried, evaporated and the residue crystallized from carbon tetrachloride to yield 2-(2-naphthyloxy) benzoic acid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C(OCC)C>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: CCOCC
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
cis,trans-Muconic acid (119 mg, 0.838 mmol) is dissolved in ethyl ether (10 mL) at room temperature and a crystal of iodine (7.2 mg, 0.028 mmol) is added. The reaction mixture is allowed to stir at room temperature for 24 hour. The precipitate is filtered, washed with ice-cold acetonitrile and dried under reduced pressure to yield 100 mg of trans,trans-muconic acid, a 84 percent yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:36]=[CH:35][C:13]([CH2:14][N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]3[CH:28]=[CH:27][C:19]4[O:20]C(C)(C)[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]3[CH:28]=[CH:27][C:19]([OH:20])=[C:18]([CH:17]=3)[C:23]([OH:24])=[O:22])=[CH:35][CH:36]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(Cl)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(Cl)cc2)cc1)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.1 %

Procedure:
To a solution of 6-({4-[(4-chlorophenyl)ethynyl]benzyl}(hexyl)amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (3.40 g, 6.77 mmol) in MeOH (150 mL) was added an aqueous solution of NaOH (5.5 mL, 5N). The reaction mixture was stirred at rt for 1.5 hr and a solid precipitated out. Water (250 mL) was added, and then the precipitate was filtered and washed with water (3×). The solid was taken up with MeOH (150 mL), an aqueous solution of NaOH (5.5 mL, 5N) was added and the resulting mixture was heated at 60° C. for 15 hrs. Then an aqueous solution of HCl (10 mL, 5N) and water (400 mL) were added and the mixture was extracted with Et2O (500+2×250 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Purification by crystallization (acetone/water) gave 909 mg (29%) of the title compound as a white powder. HPLC, Rt: 4.5 min (purity: 99.5%). LC/MS, M+(ESI): 462.0, M−(ESI): 459.9. 1H NMR (CDCl3) δ: 7.55 (d, J=8.3 Hz, 2H), 7.48 (m, 4H), 7.26 (d, J=7.9 Hz, 2H), 7.00 (d, J=2.8 Hz, 1H), 6.96 (dd, J=9.0, 2.8 Hz, 1H), 6.78 (d, J=9.0 Hz, 1H), 4.47 (s, 2H), 3.30 (m, 2H), 1.51 (m, 2H), 1.24 (m, 6H), 0.83 (m, 3H).
Reaction SMILES: [NH:1]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@@H:23]1[C:24]([O:26]CC1C=CC=CC=1)=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1>CO.[Pd]>[NH:1]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h

Procedure:
Boc-D-Tyr(Me)-L-Ile-D-Pro-OBzl (1.01 g, 1.70 mmol) was dissolved in methanol (20 ml) and subjected to catalytic hydrogenation in the presence of 5% Pd-C (150 mg). After 8 hours, the catalyst Pd-C was filtered and the reaction solution was evaporated to obtain Boc-D-Tyr(Me)-L-Ile-D-Pro-OH.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[C:57]=2[F:63])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[C:57]=2[F:63])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2F)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(Cl)c2F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-chloro-2-fluoro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 103 mg white solid (73%). MS (EI) 464.1 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[Cl:41].N1C=CC=CC=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][S:42]([C:37]4[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=4)(=[O:44])=[O:43])=[CH:28][N:27]=2)=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc2cc(Oc3ccc(N)cn3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc2cc(Oc3ccc(NS(=O)(=O)c4ccc(Cl)c(Cl)c4)cn3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.6 %

Procedure:
A stirred solution of 4-[5-(5-aminopyridin-2-yloxy)-1-methyl-1H-indole-2-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (4.69 g, 10.4 mmol) in THF (250 mL) was ice cooled, then 3,4-dichlorobenzenesulfonyl chloride (3.7 g, 15.1 mmol) and pyridine (1.51 mL, 18.7 mmol) were added to the solution. The resulting mixture was stirred for 17 hours while gradually warming up to room temperature. Water was added to the mixture, and the aqueous layer was extracted with AcOEt. The extract was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=40:1) to afford 5.26 g of the title compound as a pale yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11])=[CH:3][CH:2]=1.Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]2[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)NCCc1ccncc1
Solvent: CO
Product: O=C(O)c1csc(NCCc2ccncc2)n1
Yield: 57.2 %

Procedure:
2-(2-Pyridin-4-yl-ethylamino)-thiazole-4-carboxylic acid (236 mg) was prepared according to General Procedure B using (2-pyridin-4-yl-ethyl)-thiourea (300 mg) and 3-bromo-2-oxo-propionic acid (293 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10]O)=[S:7])(C)(C)C.Cl>CO>[CH:13]1([CH2:12][C@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)NC(=S)N[C@H](CO)CC1CCCCC1
Agent: Cl
Solvent: CO
Product: NC1=N[C@@H](CC2CCCCC2)CS1
Temperature: 100 °C
Yield: 44.6 %

Procedure:
The process is performed as in Example 1, starting with 11.1 g of N-(tert-butyl)-N′-[(1S)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea in 110 cm3 of aqueous 6N hydrochloric acid maintained at a temperature in the region of 100° C. for 2 hours. By means of an identical work-up, 3.6 g of (−)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of a white solid melting at 169° C. (αD20=−33.9±0.8 at a concentration of 0.5% in methanol).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=1.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][O:9][CH2:8][C:6]1[N:7]=[C:2]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][N:28]=2)[C:3]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:4]=2[N:5]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: COCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: COCc1nc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Heat a mixture of 4-chloro-2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine (115 mg, 0.3 mmol), 2-amino-5-trifluoromethylpyridine hydrochloride (60 mg, 0.3 mmol), xantphos (17.5 mg, 0.03 mmol), Pd2(dba)3 (27.3 mg, 0.03 mmol)and Cs2CO3 (195 mg, 0.6 mmol) in dioxane (3.0 mL) at 100° C. for 20 hours. Cool the mixture, concentrate under vacuum, dilute with water (5.0 mL), extract with EtOAc (3×3 mL) and dry with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify by flash column chromatography to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) d 3.64 (3H, s), 4.63 (2H, s), 7.41 (1H, d, J=2.1), 7.52 (1H, m), 7.81 (1H, d, J=2.1), 7.92(1H, d J=2.0), 8.15 (1H, d, J=2.0), 8.68 (1H, s), 8.88(1H, d, J=1.2), 9.02 (1H, d, J=2.2). MS =481.2 (M+H). IC50 in standard assay of capsaicin receptor activity is less than 10 nanomolar.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@@H:17]2[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C@H:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[C:10]([O:45][CH3:46])[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C@:19]3([C@@H:18]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[F:44])[C@H:17]([C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:47])=[O:5])=[CH:9][C:10]=4[O:45][CH3:46])=[O:16])[NH:21][C@H:20]3[CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.8 %

Procedure:
A solution of chiral (4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-phenyl)-acetic acid tert-butyl ester (0.16 g, 0.23 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The “pH” of the residue was adjusted to 7 by aqueous saturated NaHCO3 solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with brine, dried over MgSO4, and concentrated, dried in vacuo to give chiral (4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-phenyl)-acetic acid as a light yellow solid (0.14 g, 95%).
Reaction SMILES: [CH2:1]([C:3]1[S:44][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][C:26]=3[F:43])[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[S:44][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][C:26]=3[F:43])[C:8](=[O:23])[N:9]([CH2:12][CH:13]([OH:14])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc2c(=O)n(CC(O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a mixture of 6-ethyl-1-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[2-(4-methoxyphenyl)-2-oxoethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.77 g) and methanol (20 mL) was added sodium borohydride (0.14 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was extracted with chloroform and saturated aqueous ammonium chloride solution. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.6 g, 77%).
Reaction SMILES: [K].CCOCC.[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CCO>[CH2:15]([O:14][C:7](=[O:13])[C:8](=[O:10])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:18])[CH3:19])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])[CH3:16]
Reactant: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared by adapting the procedure described by Gagliardi S., et al., in J. Med. Chem., 1998;41:1568 using potassium (1.66 g, 42.4 mmol), Et2O (200 mL), EtOH (10 mL), diethyl oxalate (7.56 g, 51.8 mmol), and 4-tert-butyl-1-methyl-2-nitrobenzene (prepared in Example WW; 10.0 g, 51.8 mmol). MS(APCI): 294 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:14]1([CH:2]([NH:1][S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[C:3]([O:5][C@@H:6]2[CH:11]3[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]3)[CH2:7]2)=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
(R)-quinuclidin-3-yl 2-amino-2-phenylacetate (I30) (100 mg, 0.38 mmol) was dissolved in DCM (4 ml) and TEA (0.11 ml, 0.77 mmol). Benzenesulfonyl chloride (59 μl, 0.46 mmol) was added and the solution was stirred at RT for 1 hour. The volatiles were evaporated and the residue was purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.3) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(phenylsulfonamido)acetate (101 mg; 66% yield).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:19][C:20]2[C:25]3[C:26]4[CH2:34][CH2:33][C:32]5[C:28](=[CH:29][N:30]([CH2:35][CH2:36]O)[N:31]=5)[C:27]=4[S:38][C:24]=3[N:23]=[CH:22][N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.S(Br)([Br:41])=O>O>[Br:41][CH2:36][CH2:35][N:30]1[CH:29]=[C:28]2[C:32]([CH2:33][CH2:34][C:26]3[C:25]4=[C:20]([NH:19][C:7]5[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=6)=[C:5]([Cl:4])[CH:6]=5)[N:21]=[CH:22][N:23]=[C:24]4[S:38][C:27]=32)=[N:31]1
Reactant: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCl
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCc2nn(CCBr)cc2-4)ccc1OCc1ccccn1
Yield: 93.5 %

Procedure:
To 60 mL CH2Cl2 cooled to 0° C. was added 2-(6-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl)ethanol (1.60 g, 3.2 mmol), followed by thionyl bromide (2.31 g, 11.1 mmol). The contents were then stirred with warming to it over a 24 h period, after which time water (5 mL) was added to quench the reaction mixture. The solvent was removed under reduced pressure. The crude residue was diluted with aq. 2M Na2CO3 and vigorously stirred for 1 h. The precipitate was collected by filtration and triturated with methanol (30 mL) to afford the desired product (1.70 g, 94%) as a light-brown solid. 1H-NMR (DMSO-d6) δ 8.59 (d, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.82 (dd, 1H), 7.78 (s, 1H), 7.47-7.60 (m, 2H), 7.30 (dd, 1H), 7.19 (d, 1H), 5.27 (s, 2H), 4.42 (t, 2H), 3.82 (t, 2H), 3.38 (t, 2H), 2.90 (t, 2H); LCMS RT=2.89 min; [M+H]+=567.4.