Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([NH2:6])=[S:5].[C:7]1([N:13]=[C:14]=[S:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O.CC#N>[C:7]1([NH:13][C:14]([NH:3][C:4]([NH2:6])=[S:5])=[S:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: S=C=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: NC(=S)NC(=S)Nc1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To a stirring solution of NaOH (0.52 g, 13.1 mmol) in 60 mL of 10% H2O:CH3CN was added thiourea (1.0 g, 13.1 mmol). The resulting suspension was heated to 40° C. for 20 min. and then cooled to RT. To this mixture was added phenylisothiocyanate (1.5 ml, 13.1 mmol), and the clear yellow solution was stirred overnight. After stirring for 12 h, 1 N HCl was added until a white precipitate formed. The precipitate was filtered, washed with H2O, and dried under vacuum to produce the title compound as a light yellow powder (0.78 g, 30%). 1H-NMR (400 MHz, d6-DMSO) δ7.25 (t, 2H, J=7.3 Hz), 7.40 (t, 2H, J=7.9 Hz), 7.56 (d, 1H, J=7.9 Hz), 9.13-9.29 (broad singlet, 1H), and 10.26-10.79 (broad singlet, 2H).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]([C:17]([O:19]CC)=[O:18])=[C:9]([C:11]([CH2:15][CH3:16])([OH:14])[CH2:12][CH3:13])[N:10]=1)[CH2:3][CH2:4][CH3:5]>CO.C(OC(C)C)(C)C>[CH2:2]([C:6]1[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:8]([C:17]([OH:19])=[O:18])=[C:9]([C:11]([CH2:12][CH3:13])([OH:14])[CH2:15][CH3:16])[N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc(C(O)(CC)CC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CCCCc1nc(C(O)(CC)CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
1.71 ml of 1N aqueous hydrochloric acid were added to a solution of 0.65 g of ethyl 2-butyl-4-(1-ethyl-1-hydroxypropyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of methanol, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the solvent was removed by distillation under reduced pressure, and the concentrate was again dissolved in 10 ml of methanol. The resulting solution was mixed with 4.28 ml of a 1N aqueous solution of sodium hydroxide and then allowed to stand overnight at room temperature. The reaction mixture was then concentrated by evaporation under reduced pressure to remove the methanol. The pH of the concentrate was adjusted to a value of 3 by the addition of dilute aqueous hydrochloric acid, and the crystals which precipitated were collected by filtration. The crystals thus obtained were suspended in diisopropyl ether and then again collected by filtration and dried to give 0.35 g of the title compound, melting at 181°-183° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][S:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[CH:26][C:27]=1[Cl:28].O>CN(C)C=O>[CH3:14][O:13][C:11]([C:7]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][O:29][C:24]2[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=2)=[CH:10][S:9][CH:8]=1)=[O:12]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cscc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of methyl 4-(2-chloroacetamido)-3-thiophenecarboxylate ([51486-30-7], 100 mg, 0.428 mmol) in dimethylformamide (1.5 mL) was added potassium carbonate (88.7 mg, 0.642 mmol) and 3,4-dichlorophenol (83.7 mg, 0.514 mmol) and the reaction mixture was stirred at 90° C. overnight. After such time water was added. The precipitate was isolated by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (108.1 mg, 70%).
Reaction SMILES: CO.Cl([O-])(=O)(=O)=O.[CH2:8]([C:10]1([C:27]#[N:28])[C:19]2[NH+:14]([CH2:15][CH2:16][C:17]3[C:18]=2[N:20]=[C:21]2[C:26]=3[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH2:13][CH2:12][CH2:11]1)[CH3:9].[B-].[Na+]>C(Cl)Cl>[CH2:8]([C:10]1([C:27]#[N:28])[CH:19]2[N:14]([CH2:15][CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:18]=32)[CH2:13][CH2:12][CH2:11]1)[CH3:9]
Reactant: CCC1(C#N)CCC[NH+]2CCC3=c4ccccc4=NC3=C21
Agent: [B-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: CCC1(C#N)CCCN2CCc3c([nH]c4ccccc34)C21
Temperature: 5 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
In a 1-liter round-bottomed flask there were placed 200 ml methanol, 100 ml methylene chloride and 13.5 g (0.036 mole) of the perchlorate of step (c) above. The flask was cooled to about 5° C. and 5 g of sodium borohydrate were added in small quantities. The solution was then stirred for 2 hours at room temperature, concentrated, washed with water and extracted with methylene chloride. After drying and removing the solvent, there were obtained 8 g of yellow crystals, recrystallized from isopropyl ether, melted at 160° C. (yield 80%). The results of analysis are as follows:
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13](=[O:28])[CH2:14][C@H:15]3[C@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][N:16]3C(OCC=C)=O)[CH:6]=[N:5][C:4]=2[CH:3]=1.[BrH:29]>>[BrH:29].[BrH:29].[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13](=[O:28])[CH2:14][C@H:15]3[C@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][NH:16]3)[CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](O)[C@@H]1CC(=O)Cn1cnc2cc(Cl)sc2c1=O
Agent: Br
Product: O=C(C[C@@H]1NCCC[C@H]1O)Cn1cnc2cc(Cl)sc2c1=O
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
In a 15 ml single-neck round bottom flask equipped with a reflux condenser, a solution of 0.69 g (0.00162 mole) of allyl trans-2-[3-(6-chloro-3,4-dihydro-4-oxothieno[3,2-d]pyrimidin-3-yl)-2-oxopropyl]-3-hydroxy-1-piperidinecarboxylate and 6 ml of 48% aqueous hydrobromic acid was immersed in an oil bath preheated to 100° C. Heating was continued for 7.0 minutes. The solution was allowed to cool to room temperature, and the volatile components were evaporated under reduced pressure. Ethanol (5 ml) was added to the residue, and again the mixture was evaporated to dryness. This operation was repeated once more to afford a dark residue which was then triturated with a 1:1 solution of ethanol and acetone to furnish cream colored solid. The mixture was filtered, and the residue was dried under reduced pressure (about 1 mm Hg) to give the title compound: yield 0.50 g (61%); 1H-nmr (DMSO-d6) delta 1.3-2.0 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.8-3.0 (multiplet, 2H, COCH2CH), 3.1-3.6 (multiplet, 4H, NCH2, NCHCH2, CHOH), 5.2 (singlet, 2H, NCH2CO), 7.6 (singlet, 1H, thieno H), 8.4 (singlet, 1H, N=CH--N), 8.8 (broad singlet, 3H, NH2, NH).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[C:20]3([CH2:24][CH2:23][N:22]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:21]3=[O:31])[CH2:19][C@@H:18](O)[CH2:17]2)=[CH:13][CH:12]=1.C(Cl)Cl>>[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[C:20]3([CH2:24][CH2:23][N:22]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:21]3=[O:31])[CH2:19][C@H:18]([F:7])[CH2:17]2)=[CH:13][CH:12]=1
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(Cl)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1N(C2CCCCC2)CCC12C[C@H](F)CN2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethylaminosulfur trifluoride (11 μL, 0.000083 mol) was added to a solution of (3R)-1-(4-chlorobenzyl)-7-cyclohexyl-3-hydroxy-1,7-diazaspiro[4.4]nonan-6-one (10.0 mg, 0.0000276 mol; prepared as in Example 32, derived from peak 2 of step 2) in DCM (1.0 mL, 0.016 mol) at −78° C. The mixture was allowed to gradually warm to RT and stirred for 2 h. The crude reaction mixture was purified by prep. HPLC to afford the desired product. LC/MS: 365.1 (M+1H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.CN(C)C=O.C(O)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:29][C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:10]2[C:9]([CH2:8][O:7][C:6]3[CH:34]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:35])=[C:18]3[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]3[CH3:19])=[CH:12][CH:11]=2)[CH:28]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(N)cc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(2-methoxy-5-nitrophenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 6-27, 18.8 mg, 0.0392 mmol) and tin chloride (II) (23.0 mg, 0.121 mmol) was suspended in mixed solvent of anhydrous N,N-dimethylformamide (0.25 ml) and anhydrous ethanol (0.5 mL), and stirred at 80° C. overnight. After cooling down, the reaction mixture was diluted with ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution was added thereto until the pH became 9. After the precipitate was filtered, the filtrate was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (8.2 mg) as a brown solid. (Yield 47%)
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[C:24]([C:27]5[CH:28]=[N:29][C:30](OC)=N[CH:32]=5)[CH:25]=4)[NH:20][CH:19]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:35](NC(N1C2C(=C(CC3C4C(=NC=C(OC)C=4)NC=3)C=CC=2)C=C1)=O)CCC.C(NC(N1C2C(=C(CC3C4C(=NC=C(C5C=CN=CC=5)C=4)NC=3)C=CC=2)C=C1)=O)CCC>>[CH2:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[C:24]([C:27]5[CH:28]=[N:29][CH:30]=[CH:35][CH:32]=5)[CH:25]=4)[NH:20][CH:19]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(OC)cc34)cccc21
Reactant: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(-c5cnc(OC)nc5)cc34)cccc21
Agent: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(-c5ccncc5)cc34)cccc21
Product: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(-c5cccnc5)cc34)cccc21

Procedure:
The corresponding hydroxy-methyl derivative of Scheme 41 Step 2 was reacted following the protocol of Scheme 41a to prepare 4-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-indole-1-carboxylic acid butylamide P-1861, 4-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylic acid butylamide P-1876, and 4-(5-Pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylic acid butylamide P-1877, with structures shown below.
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].CCN(CC)CC.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>ClCCl>[C:25]([NH:12][C:11]1[CH:10]=[CH:9][C:8]([SiH2:7][O:6][CH2:5][CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:15][CH:16]=[CH2:17])=[CH:14][CH:13]=1)(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(N)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(CC=C)CO[SiH2]c1ccc(NC(=O)C=C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A solution of 4-(diallylethoxysilyl)aniline (153 mg, 0.62 mmol) and distilled dichloromethane (dist. CH2Cl2: 5 mL) was added with dist. Et3N (86 μL, 0.62 mmol), and then acryloyl chloride (50 μL, 0.62 mmol) was added dropwise slowly at 0° C. The mixture thus obtained was stirred under a nitrogen atmosphere at 0° C. for 8 hours. After that, the solvent in the mixture was distilled without being heated to obtain a residue. Subsequently, the residue thus obtained was separated and purified by PTLC (hexane/EtOAc=2/1) to obtain 1-acryloylamino-4-(diallylethoxysilyl)benzene (110 mg, 59% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[C:10]([O:22]C)(=O)[C:11]1[CH:20]=[CH:19][CH:18]=[C:13]([C:14]([O:16]C)=O)[CH:12]=1.Cl>O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:14]([C:13]1[CH:18]=[CH:19][CH:20]=[C:11]([C:10](=[O:22])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:12]=1)=[O:16]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1cccc(C(=O)CC(=O)C(C)(C)C)c1
Yield: 60.5 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 1.5 gm (38 mmol) of 60% sodium hydride, 3.6 gm (36 mmol) of pinacolone, 3.0 gm (15.5 mmol) of dimethyl isophthalate, and 30 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream and refluxed with heating for 6 hours. After cooling the reaction mixture, 10 ml of 2N aqueous hydrochloric acid was added the product was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give a crude product. Recrystallization using hexane afforded 3.1 gm of the target compound as colorless crystals (yield: 61%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1([C:30]2[N:35]=[C:34]([C:36]3[NH:57][C:39]4=[N:40][C:41]([N:44]5[CH2:49][CH2:48][CH2:47][C@@H:46]([C:50]([N:52]6[CH2:56][CH2:55][CH2:54][CH2:53]6)=[O:51])[CH2:45]5)=[CH:42][CH:43]=[C:38]4[N:37]=3)[CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)(C(C)(C)C)(C)C>O1CCCC1>[OH:26][C:27]1([C:30]2[N:35]=[C:34]([C:36]3[NH:57][C:39]4=[N:40][C:41]([N:44]5[CH2:49][CH2:48][CH2:47][C@@H:46]([C:50]([N:52]6[CH2:53][CH2:54][CH2:55][CH2:56]6)=[O:51])[CH2:45]5)=[CH:42][CH:43]=[C:38]4[N:37]=3)[CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)[Si](C)(C)OC1(c2cccc(-c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(C5(O)CC5)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Tetrabutylammonium fluoride (1M in tetrahydrofuran, 0.6 mL, 0.6 mmol) was added to a solution of (R)-(1-(2-(6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (89.7 mg, 0.2 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was stirred at room temperature for 40 min. The mixture was partitioned between water and ethyl acetate (3×). The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 433.1; HPLC retention time 2.1091 min (Method B).
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:30]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][CH:38]([NH2:40])[CH3:39])=[CH:34][CH:33]=1)#[N:31]>C(Cl)Cl.O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17]([NH:40][CH:38]([CH3:39])[CH2:37][O:36][C:35]1[CH:41]=[CH:42][C:32]([C:30]#[N:31])=[CH:33][CH:34]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(N)COc1ccc(C#N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)COc1ccc(C#N)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
0.5 g of N-methylpiperidine was added to a solution containing 1.0 g of (2S)-2-tert-butoxycarbonylaminobutyric acid dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -20° C., and stirred for 1 hour at -20° C. 0.9 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.0 g of the desired product in the form of a glutinous substance (yield: 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][S-:12].[Na+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:12][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cc1C=O
Yield: 63.3 %

Procedure:
(Step 1) 5-Bromo-2-fluorobenzaldehyde (15.4 g) and sodium methanethiolate (5.85 g) were stirred in N,N-dimethylformamide (30 ml) at 60° C. for 30 min. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give 5-bromo-2-(methylsulfanyl)benzaldehyde (11.1 g).
Reaction SMILES: CO[CH2:3][Br:4].[I:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][CH:11]=1.IC1C=C(O)C=CC=1C[C@@H](C(O)=O)N>C(O)(=O)C.O>[Br:4][CH2:3][C:11]1[CH:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=1[I:5]
Reactant: COc1cccc(I)c1
Reactant: COCBr
Agent: N[C@@H](Cc1ccc(O)cc1I)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CBr)c(I)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.4 %

Procedure:
Bromomethyl methyl ether (5.14 ml, 63.2 mmol) was added to a solution of 3-iodoanisole 19 (7.4 g, 31.6 mmol) in glacial acetic acid (17.0 mL) and the colorless solution was stirred for 2 days at room temperature as set forth in T. J. McCord, D. E. Thornton, K. L. Hulme and A. L. Davis, “Synthesis and Microbiological Properties of 2-Iodotyrosine and Related Compounds.” Texas J. Sci., 30, pp 357-363 (1978). The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and evaporated to produce a yellow oil which was purified by silica gel column chromatography to yield 1-bromomethyl-2-iodo-4-methoxybenzene (20) as a white solid (4.59 g, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>O1CCOCC1>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:11](=[O:14])[CH2:12][CH3:13])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 80.5 %

Procedure:
20 g (0.14 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 was dissolved in 100 ml of dioxane, and 14 g of propionyl chloride was added thereto. The mixture was allowed to react at 80° C. for 5 hours. After completion of the reaction, the dioxane was distilled off under reduced pressure, and then water was added to the residue whereby the reaction product was dissolved therein. The resulting solution was neutralized with a 10% sodium hydroxide aqueous solution whereby crystals were precipitated. The crystals were collected by filtration, washed with water and benzene, and then dried to obtain 22 g of 5-t-butyl-3-propionylaminopyrazole. This product was recrystallized from methanol and found to have a melting point of 228° to 229° C.
Reaction SMILES: [C:1]([NH:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=O)[CH2:2][CH3:3].NC1C=C2C(=CC=1)CC(NC(=O)CC)C2.Cl>>[CH3:3][CH2:2][CH2:1][NH:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: CCC(=O)NC1Cc2ccccc2C1
Agent: CCC(=O)NC1Cc2ccc(N)cc2C1
Agent: Cl
Product: CCCNC1Cc2ccccc2C1

Procedure:
2-Propionamidoindan (24, 0.83 g, 4.4 mmol) was converted to 28 (0.75 g, 98%), as described for the reduction of 25. A small amount was converted to the hydrochloride and recrystallized from 2-propanol, which yielded white crystals: mp 191-192° C.; 1H-NMR (CDCl3, 200 MHz) 1.04 (t, J=7.3, 3H), 1.70-1.82 (m, 2H), 3.01-3.20 (m, 4H), 3.29-3.48 (m, 2H), 4.00-4.11 (m, 1H), 7.18-7.30 (m, 4H); 13C NMR 9.7, 19.3, 35.5 (2C), 47.6, 58.0, 124.2 (2C), 127.0 (2C), 138.6 (2C). HRMS calcd. (obsd.) for C12H17N 175.1361 (175.1364).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](=[O:30])[NH2:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:28]([C:26]1[N:27]=[C:23]([N:21]2[CH2:22][CH:19]([OH:18])[CH2:20]2)[O:24][CH:25]=1)(=[O:30])[NH2:29]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(N)=O)co2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1coc(N2CC(O)C2)n1
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-carbamoyl-1,3-oxazol-2-yl)azetidine (1.30 g, 3.08 mmol) in tetrahydrofuran (60 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (3.1 ml) in an ice bath, and the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-(4-carbamoyl-1,3-oxazol-2-yl)-3-hydroxyazetidine (0.43 g, yield 75%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][O:29][CH:30]=4)=[C:3]([F:28])[CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccoc2)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluorobenzenesulfonamide (E105) (100 mg, 0.21 mmol) and 3-furanylboronic acid (47 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (212 mg, 1.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The solvent was evaporated with the addition of a few drops of toluene and the residue passed through an SCX column eluting with methanol followed by 2M ammonia in methanol. The basic fractions were combined and the solvent evaporated. The crude product was purified by mass directed autoprep HPLC and the relevant fractions collected and solvent evaporated to afford the title compound (E116). MS (ES+) m/e 460 [M+H]+.