Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:23]1([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:29]([C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=2[OH:11])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)c1ccc(O)c(C(C)(c2ccccc2)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 4.5 h

Procedure:
To a 500 mL three-necked flask equipped with a mechanical stirrer, 40 g of 4-tert-butylphenol, 40 g of hexanes and 1.9 g of p-toluenesulfonic acid are charged. The slurry is heated to 60° C. at which time 62 g of 1,1-diphenylethylene is added. The temperature is increased to 110° C. and the hexanes are removed by distillation. After 4.5 hours, the reaction mass is cooled to ambient temperature and purified by silica gel chromatography using heptane/ethyl acetate as the eluent. Sixty (60) grams of the title compound is obtained whose structure is confirmed by 1H nmr.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]4[CH2:25][CH2:24][O:23][CH2:22]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]5[CH2:25][CH2:24][O:23][CH2:22]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(CO[C@H]4CCOC4)n3)c2n1
Product: Nc1nc(-c2ccccc2)c2nnn(Cc3cccc(COC4CCOC4)n3)c2n1

Procedure:
This was prepared from 7-chloro-3-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and phenylboronic acid by the method of Example 13 to give 0.060 g (68%).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([C:16]([CH3:39])([CH3:38])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH:30]([CH3:37])[CH2:31][O:32]3)=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH3:39][C:16]([C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH:30]([CH3:37])[CH2:31][O:32]3)=[CH:24][CH:25]=1)=[O:18])([CH3:38])[NH2:12]
Reactant: CC1COc2cccc(Oc3ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn3)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1COc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
In a 50 ml round-bottomed flask 1,1-dimethylethyl[1,1-dimethyl-2-({6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}amino)-2-oxoethyl]carbamate (Intermediate 120, 104.0 mg) was dissolved in dichloromethane (6 ml) to give a pale yellow solution. The reaction mixture was cooled at 0° C. and TFA (2 ml, 26.0 mmol) was added. The reaction mixture was stirred at 0° C. After 2 h 30 min, the mixture was evaporated under vacuum to give the crude product which was charged on a 5 g SCX cartridge. It was then flushed with 40 ml of methanol followed by 40 ml of a 2M solution of ammonia in methanol. The ammonia eluate was evaporated under vacuum to give the title compound as a colourless oil (72.6 mg).
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C([O-])=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C1COCC1>[C:1]([O:5][C:6]([N:12]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13]1)=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of t-butyldicarbonate (21.15 g) and THF (170 ml) was added under ice cooling to a mixture of azetidine-3-carboxylic acid (9.80 g), potassium carbonate (26.8 g) and water (150 ml). After stirring the reaction mixture at room temperature for 20 hours, the mixture was adjusted to pH 4 using 2 mol/L hydrochloric acid, extracted with chloroform, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was crystallized with a mixed solution of hexane and ethyl acetate to obtain 19.5 g of 1-(t-butoxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.[Br:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>CC#N.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[N:7]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[Br:31])[CH:8]=[N:9][CH:10]=1
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: BrCc1ccccc1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCc1cncn1Cc1ccccc1Br
Temperature: 25 °C

Procedure:
To a solution of 3-(1-trityl-1H-imidazol-4-yl)propanoic acid methyl ester (5.0 g, 12.6 mmol) in CH3CN (80 mL) is added a solution of 2-bromobenzylbromide (2.84 g, 11.4 mmol) in CH3CN (20 mL). The resulting clear solution is stirred at ambient temperature over the weekend. The mixture is concentrated and the remaining oil is taken up in 85 mL methanol and heated up at 70° C. for 2 h. Then the mixture is concentrated to give a yellow oil, which is taken up in EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated to yield a viscous oil. The crude reaction mixture is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to give the desired compound. MS (ESI) m/z 323 (M+H).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>O>[C:1]1([CH:7]2[N:11]([C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[CH2:10][CH2:9][S:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: c1ccc(C2NCCS2)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C(C(Cl)Cl)N1CCSC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Five (5) grams of 2-phenyl thiazolidine was dissolved in 50 ml. of acetone, 3.1 g. of thiethylamine was added and the mixture stirred in a room temperature water bath, while 4.4 g. of dichloroacetyl chloride was added dropwise. The mixture was allowed to stand for about 30 minutes and then poured into water, extracted with methylene chloride, separated, dried over magnesium sulfate, and the solvent stripped under vacuum. There was obtained a yield of 7.3 g. of an oil, the title compound, ND30 =1.5836.
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>>[CH3:20][C:14]1[CH:13]=[C:18]([CH:17]=[CH:16][CH:15]=1)[O:19][C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1
Reactant: Cc1cccc(O)c1
Reactant: C=CCSc1ccc(Cl)nn1
Agent: [Na]
Product: C=CCSc1ccc(Oc2cccc(C)c2)nn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of dry m-cresol. To the resulting solution was added 1.87 g(0.01 mol) of 3-chloro-6-allylthiopyridazine. The reaction solution was stirred for 5 hours at 100±5° C. and then treated according to the same manner as Example 23 to obtain the title compound as a pale white needle crystal.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: COc1ncccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h
Yield: 5.2 %

Procedure:
2-(Methyloxy)-3-pyridinecarboxylic acid (33 mg, 0.22 mmol) was treated with HATU (84 mg, 0.22 mmol) in DMF (0.25 ml) and DIPEA (0.069 ml, 0.40 mmol). The reaction mixture was shaken for 5 mins prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg, 0.1 mmol) in DMF (0.25 ml) and then left to stand at room temperature for 18 h. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 ml) prior to application on to a pre-conditioned (methanol then chloroform) aminopropyl SPE cartridge (0.5 g). Product was eluted after 2 h with ethyl acetate/methanol (1:1, 3 ml), and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP(Method D) afforded the title compound (2 mg).
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH2:10][CH:9]1[OH:18])(C)(C)C.C(O)(C(F)(F)F)=O.O=C1CCC(=O)N1OC([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)=O>C(Cl)Cl>[NH2:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH:9]([OH:18])[CH:8]2[NH:7][C:6]([C:46]2[CH:47]=[CH:48][C:43]([C:40]3[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=3)=[CH:44][CH:45]=2)=[O:19])=[CH:12][CH:13]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1c2cc(N)ccc2CC1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)C(NC(=O)c1ccc(-c3ccccc3)cc1)C(O)C2
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Combine (6-amino-2-hydroxyindan-1-yl)carbamic acid tert-butyl ester (1.5 g, 5.68 mmol) with 5 mL of TFA at 0° C. Stir the mixture for 1 h and then evaporate to dryness. Added 3.0 mL of triethylamine and 30 mL of methylene chloride the residue. To this mixture, add a solution of biphenyl-4-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.76 g, 5.96 mmol) in 15 mL of methylene chloride. Stir the resulting mixture for 12 h. Evaporate solvent and purify the residue by a column chromatography (silica gel/MeOH:CH2Cl2=9:1) to give 1.88 g (96% yield) of biphenyl-4-carboxylic acid (6-amino-2-hydroxyindan-1-yl)amide; MS 345 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][N:9]2[S:13](=[O:15])(=[O:14])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[C:11](=[O:27])[CH2:10]2)=[CH:6][CH:5]=1.[C:30]([NH:37][CH2:38][C:39](O)=[O:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCN=C=NCCCN(C)C.Cl>C1COCC1>[C:33]([O:32][C:30](=[O:31])[NH:37][CH2:38][C:39](=[O:40])[NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:10][C:11](=[O:27])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[S:13]2(=[O:14])=[O:15])=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(CN)cc3)S2(=O)=O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(CNC(=O)CNC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title B compound, 5-(4-aminomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one hydrochloride (89 mg, 0.20 mmol) is suspended in dry THF (10 mL) and N-Boc glycine (42 mg, 0.24 mmol) is added. EDCl (58 mg, 0.30 mmol) is added, followed by TEA (61 mg, 0.60 mmol). The mixture is stirred at RT for 16 h. The solvent is evaporated and the residue is chromatographed on silica gel using CH2Cl2→g 3% MeOH in CH2Cl2 as the eluent to afford ({4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzylcarbamoyl}-methyl)-carbamic acid t-butyl ester as a white solid: [M+NH4]+=580.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:10]=[C:9]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: COC(=O)Cc1c[nH]c2c([N+](=O)[O-])cccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(CC(=O)OC)c2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl (7-nitro-1H-indol-3-yl)acetate from Step B (545 mg, 2.71 mmol) was added cesium carbonate (927 mg, 2.85 mmol) and methyl bromoacetate (0.26 mL, 2.84 mmol) in DMF (10 mL). The reaction mixture was stirred at ambient temperature for 18 h, then quenched with H2O (50 mL). The solid precipitate was collected by filtration to give the title compound. MS: m/z=308 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:33]4[CH:34]=[CH:22][CH:23]=[C:24]([CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:32]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1cccc(CN2CCOCC2)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4cccc(CN5CCOCC5)c4)nn23)cc1

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-morpholin-4-ylmethyl-phenyl)-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-benzyl)-morpholine (75.0 mg, 0.293 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as yellow foam (0.042 g, 35%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, J=8.5 Hz, 2H), 8.14 (d, J=8.5 Hz, 2H), 7.59-7.47 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 7.06 (dd, J=4.5, 3.9 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 6.94 (s, 1H), 3.73-3.67 (m, 4H), 3.50 (s, 2H), 3.15 (s, 3H), 2.50-2.42 (m, 4H). MS=464 (MH)+.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=[CH:9][C:8]=1[O:27][CH2:28][CH:29]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:30][O:31]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=[CH:9][C:8]=1[O:27][CH2:28][CH:29]([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:30][OH:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)c(CCCCCC)c1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(OCC(CO)OCc2ccccc2)c(CCCCCC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A solution of 11.9 g of 2-hexyl-1-(2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy)-4-tetradecylbenzene in 250 ml of chloroform was cooled to 0° C. A stream of dry hydrogen chloride gas was bubbled into the solution for 1/2 hour, then the mixture was stirred for 2 hours at 0° C. Solid sodium bicarbonate was added, the mixture stirred for 3 hours, then filtered and the chloroform evaporated. The residue was dissolved in ether, washed with aqueous sodium bicarbonate, dried and the residue chromatographed on silica gel. The column was eluted with hexane:ethyl acetate, giving 5.8 g of the desired compound, mp 32°-33° C.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.[C:9]1(=O)[CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:11]2[CH2:10]1>CO>[CH2:9]1[NH:7][CH2:10][CH:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH:12]12
Reactant: NO
Reactant: O=C1CC2c3ccccc3CC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc2c(c1)CC1CNCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (1.45 g, 17.7 mmol) and hydroxylamine hydrochloride (0.68 g, 9.75 mmol) were added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (1.4 g, 8.86 mmol) in MeOH (18 mL), and stirred overnight at room temperature. The reaction solution was concentrated via rotary evaporation. The residue was dissolved in CH2Cl2 (100 mL), washed with H2O (50 mL), dried over MgSO4, and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C11H11NO+H: 174, observed: 174.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:10](=[O:15])([O:13]C)[O:11][CH3:12].C(=O)=O>>[C:10](=[O:13])([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[O:11][CH3:12]
Reactant: COC(=O)OC
Reactant: CCCCCCCCCl
Agent: O=C=O
Product: CCCCCCCCOC(=O)OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
1-Chlorooctane (297.36 g, 1.0 mole), dimethyl carbonate (450 g, 5.0 moles) and 30.0 g of DOWEX® MWA-1 beads (Trademark of The Dow Chemical Company) are combined in a 2-liter stainless steel Paar bomb. The reactor is pressurized to 100 psi of carbon dioxide and heated with stirring to 150° C. After 2 hours, the bomb is cooled to room temperature and vented. After separating the catalyst by filtration, distillation gives 28.1 g (15 percent yield based on starting 1-chlorooctane) of methyl 1-octyl carbonate.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH3:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.[NH3:20]>>[NH2:20][CH:11]([CH3:18])[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cc2cccs2)cc1
Product: CC(N)Cc1cccs1
Temperature: 80 °C
Yield: 53 %

Procedure:
Into a 1000 ml autoclave, are added 1-(2-thienyl)-2-propanol p-toluenesulfonate (75 g) and ammonia (600 ml). The whole is heated to 80° C. during 15 hours. After cooling, the autoclave is opened and the ammonia is allowed to evaporate. After adding water (100 ml) and a 1N sodium hydroxide solution (175 ml), the resulting material is extracted with ether. The ether phase is separated and then mixed with 1N hydrochloric acid (75 ml). The aqueous phase is made alkaline and is then extracted with ether. The ether extract is washed with a 5% sodium bicarbonate solution, and then with a saturated sodium chloride solution, after which it is dried over sodium sulfate. After evaporation, the residue is distilled in vacuo, to give 19 g 2-amino-1-(2-thienyl)-propane (Yield: 53%) boiling at 84°-86° C. under 12 mm Hg.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18]([C:21](OC(C)(C)C)=O)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[N:9][CH:10]=1)=[O:4].[C:30]1(=O)[CH2:34]C[CH2:32][CH2:31]1>>[CH:21]1([N:18]2[CH2:17][CH2:16][C:15]3[CH:28]=[CH:29][C:12]([O:11][C:8]4[N:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][CH:7]=4)=[CH:13][C:14]=3[CH2:20][CH2:19]2)[CH2:32][CH2:31][CH2:30][CH2:34]1
Reactant: O=C1CCCC1
Reactant: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)cn1

Procedure:
Example 254 (E254) was prepared from N-methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide (D49) and cyclopentanone using the method described for Example 223; MS (ES+) m/e 367 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20](COC)[C:19]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[CH:18]2)[CH3:12])(=[O:10])=[O:9].Br[CH2:31][C:32]([OH:34])=[O:33].[H-].[Na+].Cl>O1CCCC1.O>[CH3:12][N:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[CH:18]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][O:1][CH2:31][C:32]([OH:34])=[O:33])(=[O:10])=[O:9]
Reactant: O=C(O)CBr
Reactant: COCn1c(-c2nccs2)cc2cccc(N(C)S(=O)(=O)c3ccsc3CO)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1COCC(=O)O
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.8 %

Procedure:
To a solution of 2-(hydroxymethyl)-N-[1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-3-sulfonamide (480 mg) and bromoacetic acid (178 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 95 mg), and the mixture was stirred at 80° C. for 12 hr. Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was stirred at 80° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (98 mg, yield 22%) as pale-yellow crystals. melting point 189° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CN([CH2:23][CH2:24][C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])N=2)C=CC=CC=1>>[C:1]1([C:7]2[N:8]([CH2:23][CH2:24][C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: C[Si](C)(C)C#CCCn1ccc(-c2ccccc2)n1
Product: C[Si](C)(C)C#CCCn1nccc1-c1ccccc1
Yield: 81 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(A), from 3-phenyl-1H-pyrazole (200 mg, 1.39 mmol) to yield 300 mg (1.12 mmol, 81%) of 5-phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole and 5-phenyl-2-(4-trimethylsilanyl-but-3-ynyl)-2H-pyrazole.