Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:30])[CH:9]=1>C1COCC1>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:1](=[O:3])[CH3:2])[CH2:34][CH2:33]2)=[O:30])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC2CCNCC2)C(COc2cccnc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)CC1
Reaction time: 16 h

Procedure:
Acetic anhydride (0.0207 mL, 0.219 mmol) was added to a solution of 4-tert-butyl 1-piperidin-4-yl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (83.7 mg, 0.199 mmol) in THF (4 mL). After 16 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 112.5 mg (98%) of the TFA salt of the desired product as a white solid. LC-MS: RT=6.40 min, [M+H]+=463.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:13][C:12]=2[F:31])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][CH2:27][C:28]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:29])=[CH:13][C:12]=2[F:31])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)CCc1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)CCc2cc(F)c(S(=O)(=O)c3ccc(Cl)cc3)nc2Cc2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 181 %

Procedure:
To a dichloromethane (3 ml) solution of 3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]propionic acid (100 mg, 0.21 mmol) were added 1-methylpiperazine (0.026 ml, 0.23 mmol), benzotriazol-1-ol (32 mg, 0.23 mmol), 4-methylmorpholine (0.026 ml, 0.23 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg, 0.23 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=19:1 eluate was concentrated under reduced pressure. The residue was dissolved in ethanol (3 ml), followed by the addition of 1N hydrochloric acid (0.224 ml). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was washed with ethanol and collected by filtration to give the title compound (111 mg, 0.19 mmol, 89%) as a white solid.
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:12]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[ClH:1].[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]2[CH2:14][CH2:15][CH:11]([CH2:10][NH2:9])[CH2:12]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C2CCC(CNCc3ccccc3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(C2CCC(CN)C2)cc1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
N-Benzyl-N-[3-(4-methoxyphenyl)cyclopentylmethyl]amine hydrochloride (6.30 g) was dissolved in acetic acid (130 ml), and 10% palladium-carbon (1.1 g) was added. After substituting the reaction vessel with hydrogen gas, hydrogen addition was carried out at normal pressure, 80° C. for 2 hours. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to produce light yellow crystals which were then washed with diethyl ether to give 4.31 g of 3-(4-methoxyphenyl) cyclopentylmethylamine hydrochloride (94.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[CH2:13]([N+](CCCC)(CCCC)CCCC)[CH2:14]CC.[OH-].[Na+].BrCCBr>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: BrCCBr
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(C2(C#N)CC2)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)acetonitrile (6.5 g, 44.1 mmol), 40% aq tetrabutylammonium hydroxide (4.5 ml) and 50% aq NaOH (30 ml) in toluene (30 ml) was added 1,2-dibromoethane (10 ml, 116 mmol) at room temperature. The reaction mixture was stirred for 16 hours, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a short silica gel column (hex:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:15]([OH:17])=O)[CH2:14][CH2:13]2)=[CH:7][C:6]=1[F:18])=[O:4].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=C=S)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([NH:29][C:15]([C:12]2([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[C:6]([F:18])[CH:7]=3)[CH2:13][CH2:14]2)=[O:17])=[CH:28][C:21]=1[C:20]([F:19])([F:32])[F:33])#[N:24]
Reactant: CNC(=O)c1ccc(NC2(C(=O)O)CC2)cc1F
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Product: CNC(=O)c1ccc(NC2(C(=O)Nc3ccc(C#N)c(C(F)(F)F)c3)CC2)cc1F
Temperature: 140 °C
Yield: 12 %

Procedure:
A mixture of 1-(4-(methylcarbamoyl)-3-fluorophenylamino)cyclopropanecarboxylic acid (200 mg, 0.79 mmol) and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (270 mg, 1.18 mmol) was heated at 140° C. for 3 h. The crude product was purified by silica gel chromatography (100-200 mesh silica, 5% acetone in DCM as eluant) to get 40 mg of 4-(1-(4-cyano-3-(trifluoromethyl)phenylcarbamoyl)cyclopropylamino)-2-fluoro-N-methylbenzamide, M+1: 421.
Reaction SMILES: [C:1](=[O:30])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]#[C:24][C:25]([O:28][CH3:29])([CH3:27])[CH3:26])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]>C(OCC)(=O)C.[C].[Pd]>[C:1](=[O:30])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH2:23][CH2:24][C:25]([O:28][CH3:29])([CH3:27])[CH3:26])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2CCC(C)(C)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of tert-butyl 2′-fluoro-5′-methoxy-2-(3-methoxy-3-methylbut-1-yn-1-yl)biphenyl-4-yl carbonate (241 mg) in ethyl acetate (5 mL) was added 10% palladium-carbon (48 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (203 mg) as a colorless oil.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][PH:18]([CH2:20]O)=[O:19])=[CH:14][CH:15]=2)[C:10]([C:22]2[N:23](C(OC(C)(C)C)=O)[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)=[CH:26][CH:25]=3)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=[O:57]>ClCCl>[N:34]1([CH2:33][CH2:32][O:31][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([C:10]2[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([O:17][P:18]([CH3:20])(=[O:19])[OH:57])[CH:12]=4)[NH:8][N:9]=2)=[CH:30]3)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3c(c2)cc(-c2nn(C(=O)OC(C)(C)C)c4ccc(O[PH](=O)CO)cc24)n3C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CP(=O)(O)Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCNCC5)ccc4[nH]3)c2c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of 39 mg of the preceding mixture containing mainly 3-{1-tert-butoxycarbonyl-5-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethoxy]-1H-indol-2-yl}-5-(hydroxymethylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester in 1 ml of dichloromethane and 200 μl of trifluoroacetic acid is stirred at 20° C. for 4 hours and the reaction mixture is then evaporated under reduced pressure. The crude compound obtained is purified by preparative LCMS, and the fractions containing the compound of molecular mass 455 are combined and evaporated under reduced pressure to yield 4 mg of methylphosphonic acid mono-{3-[5-(2-piperazin-1-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-yl}ester, which is characterized.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH:30]3[CH2:32][CH2:31]3)=[CH:22][CH:21]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH:14]([CH3:19])[C:15]([O:17]C)=[O:16])=[O:12])=[N:7][N:8]=1>C1COCC1.O>[Br:3][C:4]1[N:5]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH:30]3[CH2:32][CH2:31]3)=[CH:22][CH:21]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH:14]([CH3:19])[C:15]([OH:17])=[O:16])=[O:12])=[N:7][N:8]=1
Reactant: COC(=O)C(C)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous lithium hydroxide solution (1M, 0.8 mL, 0.8 mmol) is added to a solution of methyl 2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)propanoate (0.4 mmol) in 3:1, THF/H2O (1.6 mL) and the mixture stirred for 18 h at room temperature. The crude reaction mixture is concentrated and acidified with aqueous HCL (1M, 1.2 mL) and then is extracted with ethyl acetate (3×3 mL). The combined organic extracts are dried (sodium sulfate), filtered and concentrated to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C1COCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1I
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1c(Cl)cccc1I

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 2-chloro-6-iodobenzoic acid (2.7 g, 9.6 mmol), oxalyl chloride (1.4 g, 11.5 mmol), ammonia gas, THF (20 mL) and DCM (10 mL) to afford 2.3 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.11 (t, J=7.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.00 (s, 1H); MS (m/z): 281.98 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:9]2[C:10](=[O:12])[CH2:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:13])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 24.6 %

Procedure:
In accordance with the synthesis process (B), 500 mg (2.84 mmol) of 1-phenyl-imidazolidin-2,4-dione were dissolved in 20 ml of pyridine. To the solution, 500 mg (2.86 mmol) of p-chlorobenzoyl chloride were added dropwise while chilling with ice water. The resultant mixture was stirred at 0°-5° C. for 2 hours, and dilute hydrochloric acid was then added to the reaction mixture. Crystals deposited were collected by filtration by means of suction. These crude crystals were recrystallized from n-hexane/ethyl acetate, thereby obtaining 220 mg (yield: 25%) of the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([NH:13][C:14]3[N:19]4[C:20]([CH3:26])=[C:21]([C:23](O)=[O:24])[CH:22]=[C:18]4[CH:17]=[N:16][N:15]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.CCN(CC)CC>[CH2:49]([NH:56][C:23]([C:21]1[CH:22]=[C:18]2[CH:17]=[N:16][N:15]=[C:14]([NH:13][C:11]3[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:3][CH2:2]4)[CH:8]=[CH:9][C:10]=3[CH3:27])[N:19]2[C:20]=1[CH3:26])=[O:24])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Nc1nncc2cc(C(=O)O)c(C)n12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1Nc1nncc2cc(C(=O)NCc3ccccc3)c(C)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-6-methyl-pyrrolo[1,2-d][1,2,4]triazine-7-carboxylic acid (37, 0.13 mmol) in DMF (1 mL) was added EDCI (37 mg, 0.20 mmol), HOBt (30 mg, 0.20 mmol), Et3N (45 μL) and benzylamine (29 μl, 0.27 mmol). The reaction mixture was stirred for 3 h at rt. The crude material was purified by preparative HPLC to give the titled product, 3.3 mg as an off white solid. HPLC (condition A) tR 4.40 min. MS m/z 455 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:45]
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: Cc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3N3CC[C@@H](F)[C@@H](N)CC3)c(N)s2)c1

Procedure:
Following the procedure for Example 221 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxylic acid gave, after purification via silica gel column chromatography (5% MeOH/DCM with 1% 7 N ammonia in MeOH), 294 as a cream solid (107 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.90-7.84 (m, 1H), 7.82 (s, 1H), 7.17-7.11 (m, 1H), 7.04 (dd, J=11.1, 8.4 Hz, 1H), 6.10 (s, 2H), 4.95-4.78 (m, 1H), 3.74 (s, 3H), 3.49-3.33 (m, 3H), 3.24-3.11 (m, 2H), 2.40 (s, 3H), 2.40-2.26 (m, 1H), 2.09-1.91 (m, 2H), 1.87-1.77 (m, 1H). Alkyl NH2 not seen. LCMS (ES+) m/z 462 (M+1)
Reaction SMILES: [F:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][NH:5][C:6](=[O:32])[N:7]([C@H:9]([CH2:17][O:18][C:19](=[O:31])[NH:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH3:8].[Li+].[OH-].Cl>O1CCOCC1>[F:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][NH:5][C:6](=[O:32])[N:7]([C@H:9]([CH2:17][O:18][C:19](=[O:31])[NH:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH3:8]
Reactant: COC(=O)CCC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)NCc1cccc(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCC(=O)O)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 5-(3-(2,3-difluorobenzyl)-1-methylureido)-6-(isoquinolin-3-ylcarbamoyloxy)hexanoate (1.45 g, 2.04 mmol, 1.0 equiv.) in 1,4-dioxane (18 mL) was added aqueous LiOH (6.12 mL, 6.12 mmol, 3.0 equiv.) at RT After stirred at RT for 1 h, the reaction mixture was acidified with HCl (1.0 N) to pH ˜3. The mixture was extracted with EtOAc twice. The combined EtOAc solution was washed with brine, dried over Na2SO4, and concentrated under vacuum to give (S)-5-(3-(2,3-difluorobenzyl)-1-methylureido)-6-(isoquinolin-3-ylcarbamoyloxy)hexanoic acid, which was used without further purification. LRMS (M+H+) m/z 501.3.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=O)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:12][O:11][C:9](=[O:10])[C:8]1[C:7](=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: Nc1ccccc1
Product: COC(=O)c1ccccc1Nc1ccccc1

Procedure:
Reaction of methyl 2-(trifluoromethanesulfonyloxy)benzoate with aniline according to general procedure A provided methyl ester of 2 as a yellow oil (99% yield). 1H NMR (CDCl3, 500 MHz): δ=9.48 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.22-7.40 (m, 6H), 7.10 (t, J=7.3 Hz, 1H), 6.74 (t, J=7.5 Hz, 1H), 3.91 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=169.1, 148.2, 141.0, 134.3, 131.8, 129.6, 123.8, 122.8, 117.3, 114.3, 112.2, 51.9.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][NH:9][C:10]([CH:12]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14][S:13]2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][NH:9][C:10]([CH:12]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:14][S:13]2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCSC1C(=O)NCc1ccc(N)cc1

Procedure:
A spatula tip's worth of Nickel of Raney is added to a solution of 1.25 g (3.4 mmoles) of N-(4-nitrobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide in 2.5 ml of methanol. The whole is taken to reflux and hydrazine hydrate (1.75 ml) is added dropwise to the medium. The reaction is maintained for 1 hour under reflux, then returned to ambient temperature. The catalyst is filtered off and abundantly rinsed with methanol. The solvent is evaporated off under reduced pressure. Then the residue is taken up in dichloromethane (20 ml) and washed 3 times with 15 ml of water. The organic phase is dried and the solvent is evaporated off under reduced pressure. N-(4-aminobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide is obtained in the form of an inert yellow solid (0.815 g, 71%); it will be used in following stages without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O[CH:31](N(C)C)[N:32]([CH3:34])[CH3:33])(C)(C)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15][C:14](=[O:17])/[C:13](=[CH:31]/[N:32]([CH3:34])[CH3:33])/[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCC(=O)CC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)/C=C1\CC(NC(=O)OC(C)(C)C)(c2cccc(C(C)(C)C)c2)CCC1=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 1-(3-tert-butylphenyl)-4-oxocyclohexylcarbamate (691 mg, 2.0 mmol) in Toluene (5 mL) was added tert-butoxybis(dimethylamino)methane (454 μL, 2.2 mmol). The reaction was stirred at 85° C. overnight. The reaction was concentrated and used crude in the next step.
Reaction SMILES: [C:1]([O:15]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=O.[NH:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][OH:23])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([N:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20])=[O:15]
Reactant: COC(=O)CCCCCCCCC(=O)OC
Reactant: OCCNCCO
Product: O=C(CCCCCCCCC(=O)N(CCO)CCO)N(CCO)CCO
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 57.58 g (0.25 mol) dimethyl sebacate and 157.71 g (1.50 mol) of diethanolamine was heated in a 140° C. bath under nitrogen for 2.5 hrs while collecting the methanol condensate. The reaction mixture was subsequently heated in a 200° C. at reduced pressure (1.5 mm) to distill off excess diethanolamine. The highly viscous oily residue was dissolved in an equal volume of acetone and stirred overnight. The resulting crystalline solid was collected, washed with acetone, and dried. The yield of product was 35.0 g (9.3% of theory); mp=87-98° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:3]2[C:4]([NH:8][C@H:9]([C:11]3[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15](=[O:23])[C:14]4=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]4[N:12]=3)[CH3:10])=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])=[CH:38][N:39]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cnc(N)nc3)n(-c3ccccc3)c(=O)c12
Yield: 19.1 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (34 mg, 0.15 mmol), 1,1% bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.43 mol) according to the method described in Example 3 to give 13 mg (28% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=[O:30])=[N:26][C:27](Cl)=[O:28]>C1COCC1>[CH2:1]([N:8]1[C:27](=[O:28])[NH:26][C:25](=[O:30])[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[C:19]([CH3:24])=[N:20][O:21][C:22]=3[CH3:23])[CH:16]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCc2ccccc2)cn1
Reactant: O=C=NC(=O)Cl
Solvent: C1CCOC1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]c(=O)n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)urea (example 95b) (100 mg, 0.31 mmol) in THF (2 mL) was cooled to 0° C. and n-chlorocarbonyl isocyanate (97 mg, 0.92 mmol) was slowly added. After addition, the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction was concentrated and the residue was purified by silica column chromatography (100% to 90% dichloromethane in methanol:30 minute gradient) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazinane-2,4,6-trione (112 mg, 93%) as a white solid. 1H NMR (DMSO-d6, 400 MHz)): δ2.12 (s, 3H), 2.38 (s, 3H), 4.87 (s, 2H), 5.16 (s, 2H), 7.23-7.34 (m, 5H), 7.45 (s, 1H), 7.90 (s, 1H), 11.93 (s, 1H). LC/MS; [M+H] calculated for C19H18N6O4; expected 395.14. found 395.15. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.14 μM.