Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.[NH2:29][NH2:30].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[NH:30][N:29]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(Cc2ccccc2)C(=O)c2ccc(OC)cc2)cc1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(-c3ccc(OC)cc3)c2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 1 (1.0 equiv.), hydrazine (3.0 equiv.), conc. HCl aq. (catalytic amount) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCl, brine, dried, filtered and the solvent was concentrated in vacuo to give the product 4-methoxy-1-[5-(4-methoxyphenyl)-4-benzylpyrazol-3-yl]benzene.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=3)[C:6]([CH3:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][C:31]3=[O:43])[CH:25]=[N:26][CH:27]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C.CN(C=O)C.C(N(CC)CC)C>[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:34][CH2:35][N:36]([C:13]([C:10]4[CH:11]=[C:12]5[C:7]([C:6]([CH3:18])=[CH:5][N:4]5[CH:1]5[CH2:2][CH2:3]5)=[C:8]([O:16][CH3:17])[CH:9]=4)=[O:15])[CH2:37][CH2:38]2)[CH2:32][C:31]3=[O:43])[CH:25]=[N:26][CH:27]=1
Reactant: COc1cc(C(=O)O)cc2c1c(C)cn2C1CC1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3cncc(Br)c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(Br)c4)ccc2O3)cc2c1c(C)cn2C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylamine (0.33 mL) was added to a DMF (7.5 mL) solution of 1-cyclopropyl-4-methoxy-3-methyl-1H-indole-6-carboxylic acid (147 mg), 6-(5-bromo-3-pyridinyl)spiro-[chroman-2,4′-piperidin]-4-one dihydrochloride (268 mg), WSC hydrochloride (164 mg) and HOBT (110 mg), and stirred at r.t. for 5 h. This reaction mixture was diluted with ethyl acetate, then washed with water, aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with sodium sulfate. This was filtered, concentrated, and purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance. 1H-NMR (400 MHz, DMSO-d6) δ: 8.86 (1H, d, J=2.0 Hz), 8.66 (1H, d, J=2.0 Hz), 8.36 (1H, t, J=2.0 Hz), 8.05-7.99 (2H, m), 7.24 (1H, d, J=8.6 Hz), 7.13 (1H, s), 7.00 (1H, s), 6.50 (1H, s), 4.40-4.08 (1H, br m), 3.83 (3H, s), 3.78-3.22 (4H, br m), 2.94 (2H, s), 2.31 (3H, s), 2.04-1.75 (4H, br m), 1.03-0.97 (2H, m), 0.89-0.84 (2H, m); MS [M+H]+=600, 602.
Reaction SMILES: [CH:1]([NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:27]([O:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:28])=[CH:23][CH:24]=2)[C:19]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[CH:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[C:59]1([CH3:69])[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[S:65]([NH2:68])(=[O:67])=[O:66]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]([NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:27]([O:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:28])=[CH:23][CH:24]=2)[C:19]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([NH:68][S:65]([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=3[CH3:69])(=[O:67])=[O:66])=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[CH:18]1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C(=O)NC(c2ccccc2)c2ccccc2)c2ccc(NC(=O)OC3CCCC3)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C(=O)NC(c2ccccc2)c2ccccc2)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.9 %

Procedure:
To a solution of 4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.50 grams, 0.81 mmol), 4-dimethylaminopyridine (0.015 grams, 1.21 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (0.23 g, 1.21 mmol) in methylene chloride (30 mL) was added o-tolylsulfonamide (0.14 g, 0.81 mmol). The resulting solution was stirred for 12 hours at room temperature. The solution was diluted with methylene chloride and washed with 1 M hydrochloric acid (aq). The organics were dried over magnesium sulfate and concentrated. Chromatography on silica gel (2% methanol/methylene chloride), followed by recrystallization from wet ether gave the titled compound (0.455 grams, 73% yield). m.p.=253-254° C. Anal. calcd. for C44H42N4O7S: C, 68.55; H, 5.49; N, 7.27. Found: C, 69.21; H, 5.54; N, 7.14. HRMS calcd. for C44H42N4O7S: 770.2774. Found 770.2736.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][C:32]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br.Cl>CN(C)C=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:32]=3[CH3:31])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Cc1ccc(CBr)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)c(C)c1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2,4-dimethylbenzyl bromide (400 mg, 2.0 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (173 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.15 (br. s., 1 H), 2.31 (s, 3 H), 2.18-2.29 (m, 5 H), 1.78 (d, J=13.14 Hz, 2 H), 1.62 (d, J=10.36 Hz, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.12 (t, J=12.88 Hz, 1 H).
Reaction SMILES: C(OP(Cl)(OCC)=O)C.[CH3:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13](=O)[C:12]1=[O:22].[N+:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[C-:24].O>CN(C)C=O>[CH3:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:24]=[N:23][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]2[C:12]1=[O:22]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cn1c(=O)c(=O)[nH]c2ccccc21
Agent: CCOP(=O)(Cl)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1c(=O)n(C)c1ccccc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
6.2 ml of diethylchlorophosphate was added to a mixture of 5.3 g of 1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline and of 4.5 g of K-t-butoxide in 50 ml dimethyl formamide (DMF) at room temperature. The resulting mixture was heated until it formed a solution and was then cooled to -30° C. A -30° C. cold mixture of 4.8 g of K-t-butoxide and 4.5 ml of ethyl isocyanoacetate in 20 ml of dry DMF was added to this solution. The resulting mixture was stirred for one hour at room temperature. Then 100 ml of water was added and the mixture was filtered. The resulting residue was crystallized leaving 2.5 g of the title compound. M.p. 218.5°-219.8° C.
Reaction SMILES: I[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:31]=1)[C:25](N(OC)C)=[O:26]>C(OCC)C>[Br:19][C:20]1[CH:31]=[C:24]([C:25]([C:2]2[C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:5]=3[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=2)=[O:26])[CH:23]=[N:22][CH:21]=1
Reactant: CC(C)n1cc(I)c2cnccc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Reaction time: 0.5 h

Procedure:
To a mixture of 3-iodo-1-isopropyl-1H-pyrrolo[3,2-c]pyridine (Preparation 45, 13 g, 45.43 mmol) in anhydrous diethyl ether (120 mL) at −78° C. was added nBuLi (28.69 mL, 54.5 mmol) dropwise under nitrogen. After stirring at this temperature for 30 minutes, 5-bromo-N-methoxy-N-methylnicotinamide (11.13 g, 45.43 mmol) in diethylether (10 mL) was added dropwise before warming the reaction to room temperature for 18 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted into EtOAc, the organic layer collected, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 80-90% EtOAc in hexanes to afford the title compound as a yellow solid.
Reaction SMILES: [C:1](=[C:4]1[CH2:9][CH2:8][C:7]([CH2:11][OH:12])([CH3:10])[CH:6]=[CH:5]1)([CH3:3])[CH3:2]>[Pd].C(O)(C)C>[CH:1]([C:4]1[CH2:9][CH2:8][C:7]([CH2:11][OH:12])([CH3:10])[CH2:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)=C1C=CC(C)(CO)CC1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)C1=CCC(C)(CO)CC1
Reaction time: 4.5 h
Yield: 73 %

Procedure:
A glass reaction vessel was charged with 10 g of 4-isopropylidene-1-methyl-2-cyclohexenylmethanol produced by the same method as used in Example 1, 0.05 g of 5% Pd/C (water content: 53%) and 20 mL of isopropanol, and the contents of the reaction vessel were reacted with each other at a pressure of from 0.1 to 0.4 MPa and a temperature of 30° C. for 4.5 h. Thereafter, at the time at which the amount of hydrogen consumed reached 1.2 moles per 1 mole of the raw material, the reaction was stopped, and the reaction mixture was filtered to remove the catalyst therefrom, and then concentrated to obtain 4-isopropyl-1-methyl-3-cyclohexenylmethanol with a yield of 73%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([OH:15])(=[O:14])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][S:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:31][CH2:30]1>C(N(CC)CC)C.ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([NH:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][S:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:31][CH2:30]2)(=[O:14])=[O:15])=[CH:4][CH:3]=1
Reactant: NCCN1CCN(CCCSc2ccccc2)CC1
Reactant: O=S(=O)(O)c1ccc(Cl)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(NCCN1CCN(CCCSc2ccccc2)CC1)c1ccc(Cl)c2ncccc12
Temperature: 0 °C
Yield: 72 %

Procedure:
To 14.2 g of 8-chloro-5-quinolinesulfonic acid were added 142 ml of thionyl chloride and 1.42 ml of dimethylformamide. The resultant mixture was heated under reflux for 3 hours and the thionyl chloride was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was dissolved in 100 ml of ice water and adjusted to a pH of 6 with a saturated aqueous sodium carbonate solution, followed by extraction with 100 ml of dichloromethane to obtain a dichloromethane phase. The dichloromethane phase was added dropwise to 100 ml of a dichloromethane solution containing 16.3 g of 1-(2-aminoethyl)-4-[3-(phenylthio)propyl]piperazine and 6.5 g of triethylamine over 30 minutes while cooling with ice. The resultant mixture was stirred at a temperature of 15° C. to 20° C. for 2 hours to carry out a reaction. After completion of the reaction, the resultant mixture was washed with 200 ml of water and dried over anhydrous magnesium sulfate. Then, solvent removal was conducted by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 250 g of silica gel (Wakogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan), using a mixed solvent comprised of methanol and chloroform (2% methanol) as an eluent, to thereby obtain 21.2 g of 1-(8-chloro-5-quinolinesulfonylaminoethyl)-4-[3-(phenylthio)propyl]piperazine (1) (yield: 72%) .
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2.[OH-].[Na+]>O1CCCC1.CN(C)C=O.N1C=CC=CC=1>[O:22]=[C:16]1[CH2:15][C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:17]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1Cc2c(CCO)cccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1Cc2c(CCOC(=O)Nc3ccccc3)cccc2N1
Temperature: 70 °C
Yield: 80.4 %

Procedure:
Phenyl isocyanate (0.652 mL, 6 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL), dimethylforamide (2 mL) and pyridine (3 drops). The mixture was heated at 70° C. for 15 hours. The reaction was cooled, poured into 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with 1 N hydrochloric acid (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol/ethyl acetate/hexane to give 953 mg (80%) of phenyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as an off-white powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[S:7](=[O:11])(=[O:10])[CH2:8][CH2:9][C:5]=2[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[S:7](=[O:11])(=[O:10])[CH2:8][CH2:9][C:5]=2[CH:4]=1
Reactant: O=S1(=O)CCc2cc(CO)ccc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S1(=O)CCc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.8 %

Procedure:
To a solution of 5-hydroxymethyl-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (185 mg, 0.93 mmol) in CH2Cl2 (6 mL) was added triphenylphosphine (294 mg, 1.12 mmol) and carbon tetrabromide (371 mg, 1.12 mmol). After stirring for 14 h at rt, all volatiles were removed under reduced pressure. 5-Bromomethyl-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (218 mg, 90%) was isolated by chromatography (33-50% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17](C(OCC)=O)=[C:16]([CH3:23])[N:15]=[C:14]3[S:24][C:25]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:26][C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].C(O)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:23])[N:15]=[C:14]3[S:24][C:25]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:26][C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2cc(-c3cn[nH]c3)sc2n1
Temperature: 150 °C
Yield: 23.1 %

Procedure:
A mixture of ethyl 4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridine-5-carboxylate (Description 73) (250 mg, 0.524 mmol) in DMSO (5 mL) and aqueous NaOH (2M) (1.048 mL, 5.24 mmol) was heated at 150° C. for ca. 1 h. After cooling to RT, the mixture was diluted with water (20 mL) and acidified with formic acid (pH ca. 4-5). The mixture was extracted with 10% MeOH in DCM (30 mL×5) and the combined organics dried and concentrated. The residue was passed through a C18 solid phase extractor cartridge, eluting with water (100 mL×4) and then with MeOH (100 mL×4) and the combined organics concentrated. The residue was taken-up in diphenyl ether (2.501 mL, 15.72 mmol) and DMSO (0.5 mL) and the mixture heated at 200° C. for ca. 45 min. After cooling to RT, the mixture was purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in cyclohexane followed by a gradient of 0-10% MeOH in DCM and then further purified by MDAP (basic conditions), to give the title compound (49 mg). LCMS (A) m/z: 405 [M+1]+, Rt 0.98 min (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:13]([O:15]CC)=[O:14])=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:13]([OH:15])=[O:14])=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=1
Reactant: CCOC(=O)c1c(C)nc2cc(OC)ccn12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccn2c(C(=O)O)c(C)nc2c1

Procedure:
To a solution of ethyl 7-methoxy-2-methylimidazo[1,2-α]pyridine-3-carboxylate (1.8 g, 7.7 mmol) in THF (100 ml) and MeOH (50 ml) was added aq. NaOH (11.5 ml, 2M, 23.1 mmol) and the resulting emulsion heated to reflux for 2 hours. A further aliquot of NaOH was then added (3.8 ml, 2M, 7.7 mmol) and the resulting mixture heated for a further 2 hours. The solvents were removed in-vacuo and the residue was acidified with 1.5 N HCl to pH 3, and the resulting solid was filtered off, washed with water and dried in vacuo to yield 7-methoxy-2-methylimidazo[1,2-α]pyridine-3-carboxylic acid, 1.2 g, 76%, as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:24][S:25]([O:15][CH2:14][C@@H:12]1[O:11][C:10](=[O:16])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1)(=[O:27])=[O:26]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (Intermediate 3, 25.0 g, 74.2 mmol) was stirred in dichloromethane (250 ml) at 0° C. Triethylamine (10.5 g, 104 mmol) was added followed by methanesulfonyl chloride (11.2 g, 89.0 mmol) and the reaction was stirred overnight, slowly warming to room temperature. The yellow solution was diluted with sodium bicarbonate and the compound was extracted using dichloromethane (3×250 ml). The organic layer was dried (magnesium sulfate), filtered and concentrated to give the desired product as a light yellow solid (30.3 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:26][CH2:25]N5C[CH2:28][CH2:29][C@H:23]5[CH2:22]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.Cl.C(O[C:42]([N:44]1CC2(CCNCC2)C1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:42]1[C:29]2([CH2:23][CH2:22][N:21]([CH2:20][C:18]3[S:19][C:14]4[C:13]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[N:12][C:11]([C:4]5[CH:3]=[C:2]([F:1])[CH:10]=[C:9]6[C:5]=5[CH:6]=[CH:7][NH:8]6)=[N:16][C:15]=4[CH:17]=3)[CH2:26][CH2:25]2)[CH2:28][NH:44]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN5CCC[C@H]5C4)cc3n2)c2cc[nH]c2c1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCC5(CC4)CNC5)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 2-(6-fluoro-1H-indol-4-yl)-6-[(S)-1-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno-[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride in place of (S)-octahydro-pyrrolo[1,2-a]pyrazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (27 mg, 44%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:3]=[N:2]1.Cl[CH2:18][C:19]1[C:20]([CH3:25])=[N:21][O:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:25][C:20]1[C:19]([CH2:18][N:1]2[CH:5]=[C:4]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])[CH:3]=[N:2]2)=[C:23]([CH3:24])[O:22][N:21]=1
Reactant: Cc1noc(C)c1CCl
Reactant: O=C1c2ccccc2C(=O)N1c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)c3ccccc3C2=O)cn1
Yield: 39.9 %

Procedure:
2-(1H-pyrazol-4-yl)isoindoline-1,3-dione (example 9-1a) (1.5 g, 7 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (1.5 g, 10 mmol), and cesium carbonate (3.3 g, 10 mmol) were stirred in DMF (20 mL) at 80° C. for 3 hours. The reaction was cooled, diluted with H2O (150 mL), and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The solid product was triturated with ethyl acetate/hexanes (1/9) and re-crystallized from refluxing absolute ethanol (30 mL) to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindoline-1,3-dione (900 mg, 38%) as a bright, light yellow solid. 1H NMR (DMSO-d6, 400 MHz) 1.36 (d, 3H, δ J2.16 (s, 3H), 2.41 (s, 3H),=7.2 Hz), 5.22 (s, 2H), 7.81 (s, 1H), 7.91-7.83 (m, 4H), 8.21 (s, 1H). MS M+H calculated 323.11; found 323.1. Melting point: 170-171° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.18 μM.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH:13]([CH3:16])[CH2:14][OH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:6]([CH:13]([CH3:16])[CH2:14][O:15][S:1](=[O:4])(=[O:3])[NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(CO)Oc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: CC(COS(N)(=O)=O)Oc1ccccc1

Procedure:
The title compound was prepared by procedures of Example 28 from sulfamoyl chloride and 2-phenoxypropanol. The oil obtained was further purified as in Example 28 by chromatography and recrystallization to give the title compound as colorless, viscous oil in 35% yield.
Reaction SMILES: [F:1][C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[C:3]([F:14])([F:13])[C:4]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:12])[NH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:42][C:39]1[CH:38]=[CH:37][C:36]([N:33]2[CH2:32][CH2:31][N:30]([C:28](=[O:29])[CH2:27][N:6]3[C:7]([CH3:12])=[C:8]([N+:9]([O-:11])=[O:10])[C:4]([C:3]([F:13])([F:14])[C:2]([F:1])([F:19])[C:15]([F:17])([F:18])[F:16])=[N:5]3)[CH2:35][CH2:34]2)=[CH:41][CH:40]=1
Reactant: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1[N+](=O)[O-]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1c([N+](=O)[O-])c(C(F)(F)C(F)(F)C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7) afforded the title compound as oil. 1H NMR (400 MHz, CDCl3): 6.9–7.0 (m, 2H), 6.8–6.9 (m, 2H), 5.06–5.14 (d, 2H), 3.6–3.8 (m, 4H), 3.06–3.18 (m, 4H), 2.56–2.66 (d, 3H). 13C NMR (400 MHz, CDCl3): 160, 146.2, 144, 119.2, 118, 52.2, 50.8, 50.4, 46, 42.2, 12.