Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:21]=1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:2]([NH:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[CH:21]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a 25 ml flask was added (S)-tert-butyl 1-oxo-3-phenyl-1-(3-(pyridin-4-yl)isoxazol-5-ylamino)propan-2-ylcarbamate 3.3B (160 mg, 0.40 mmoles), 10 ml of CH2Cl2, and 5 ml of TFA. The reaction was stirred at room temperature for 3 hour at which time the solvent was removed with a stream of nitrogen. The crude material was then partitioned between 200 ml of DCM and 100 ml of saturated sodium bicarbonate. The organic solvent was removed by rotary evaporation to give (S)-2-amino-3-phenyl-N-(3-(pyridin-4-yl)isoxazol-5-yl)propanamide 3.3.C as a light yellow solid (100 mg, 81% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=O.[NH3:21]>CO>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:11]2[NH:21][C:3](=[O:2])[C:5]3[S:6][CH:7]=[CH:8][C:9]=3[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1sccc1NC(=O)c1cccc(OC)c1
Reactant: N
Solvent: CO
Product: COc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1

Procedure:
3-(3-Methoxy-benzoylamino)-thiophene-2-carboxylic acid methyl ester, 24, (12.78 g) was added to methanol (200 mL) previously saturated with ammonia. The mixture was placed in a bomb reactor, and heated to 100° for 2 days. The solvent was then removed in vacuo and the resulting residue was suspended in isopropanol (250 mL); 2M sodium hydroxide solution was then added (83 mL), and the mixture was heated to reflux for 5 hours. The reaction mixture was then cooled and acidified to pH 1. 2-(3-methoxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one, 25, (12.16 g) was collected as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42](Cl)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1>N1C=CC=CC=1>[F:28][C:29]([F:45])([F:46])[C:30]1[CH:31]=[CH:32][C:33]([C:36]2[C:37]([C:42]([N:1]3[CH:5]=[CH:4][C:3]([C:6]4[CH:11]=[CH:10][C:9]([C:12]([N:14]5[C:20]6[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=6[CH2:18][N:17]6[CH:25]=[CH:26][CH:27]=[C:16]6[CH2:15]5)=[O:13])=[CH:8][CH:7]=4)=[N:2]3)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)n2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 48.9 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (20 ml) and 4′-trifluoromethyl-2-biphenylcarbonyl chloride (0.71 g), the title compound (0.59 g) was obtained as an amorphous solid, MS, m/z: 602 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].CN(C)C1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35].Cl>C1(C)C=CC=CC=1>[C:34]([N:5]([CH2:4][C:3]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=1[Cl:1])[C:6]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(C(=O)OC)c(NCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(N(Cc2ccc(Cl)cc2Cl)C(C)=O)c1
Temperature: 50 °C

Procedure:
A mixture of dimethyl 2-(2,4-dichlorobenzyl)aminoterephthalate (12.00 g), N,N-dimethylaniline (7.92 g) and acetyl chloride (5.5 ml) in toluene (140 ml) was heated at 50° C. for 15 hr. After cooling, ice and concentrated hydrochloric acid were added to acidify the reaction mixture and the toluene layer was separated. The toluene layer was washed successively with water and a saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and concentrated. The residue was crystallized from 2-propanol to give the objective compound (8.40 g) as white crystals.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:15]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[O:17]=[C:18]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:37](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:30]1([C:23]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:21][CH2:20][N:19]([CH2:36][C:37]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=4)[N:15]=3)[C:18]2=[O:17])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [H]/N=C(\NO)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(OC(F)(F)F)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
(Z)—N-Hydroxy-4-(trifluoromethoxy)benzimidamide (0.125 g, 0.566 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.175 g, 0.566 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.163 g, 0.849 mmol) were stirred together in dichloroethane (4 mL) at room temperature for 45 minutes, then heated to 85° C. and stirred for 16 hours. The reaction was cooled and concentrated. Silica gel chromatography using a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) eluting with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=35 mL/minute) over 30 minutes gave the title compound. 1H NMR (300 MHz, CDCl3) δ 8.22-8.08 (m, 2H), 7.43-7.16 (m, 12H), 4.92 (s, 2H), 3.62 (t, J=6.5, 2H), 2.80-2.61 (m, 2H), 2.03-1.80 (m, 2H); MS (ESI+) m/z 494.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[C:24]([O:23][C:21](=[O:22])[CH2:20][N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1c(-c2cccnc2)n(CC(=O)OC(C)(C)C)c2ccc(C#N)cc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) and tert-butyl bromoacetate are processed according to the method described in Example 68 to give (5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-acetic acid tert-butyl ester. 1H NMR (400 MHz, MeOD) δ ppm 1.38 (s, 9H), 2.31 (s, 3H), 4.83 (s, 2H), 7.56 (d, J=1.3 Hz, 2H), 7.66 (ddd, J=7.8, 4.9, 0.9 Hz, 1H), 7.95 (dt, J=7.8, 1.9 Hz, 1H), 8.09 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 8.71 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 348.1719 [(M+H)+ Calcd for C21H22N3O2: 348.1712].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)=O.[CH3:24][NH:25][NH2:26].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=4)[CH:13]=3)=[N:26][N:25]2[CH3:24])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)c2ccc3cc(OC)ccc3c2)c(F)c1
Reactant: CNN
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2cc(-c3nn(C)c4cc(OC)ccc34)ccc2c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
A mixture of (2-fluoro-4-methoxyphenyl)(6-methoxy-2-naphthyl)methanone (1.0 g, 3.22 mmol), 1-methylhydrazine (0.74 g, 16.1 mmol), pyridine (10 mL), and 4-dimethylaminopyridine (0.39 g, 3.22 mmol) was stirred at 100° C. for 12 h. The mixture poured in the water, extracted with ethyl ether, washed with HCl (2N), and dried over MgSO4. Evaporation and crystallization from ethyl ether/hexanes gave an off-white solid (0.82 g, 80% yield, m.p. 166-168° C.); MS m/e 319 (M+H)+.
Reaction SMILES: [CH:1]12[O:10][CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O)(=O)=O.O.C(#[N:19])C>C(Cl)Cl>[NH2:19][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: CC#N
Reactant: c1ccc2c(c1)CC1OC21
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -20 °C

Procedure:
Indene oxide (117 g) diluted to a total volume of 600 mL in methylene chloride was diluted with acetonitrile (600 mL) and cooled to -20° C. Methanesulfonic acid (114 mL) was then added. The mixture was warmed to 25° C. and aged for 2 h. Water (600 mL) was added and the mixture heated at 45° C. for 5 h. The organic phase was separated and the aqueous phase further heated at reflux for 4 h with concentration to approximately 200 g/L. The solution was adjusted to pH 12.5 with 50% aqueous sodium hydroxide, and then cooled to 5° C. and filtered, dried in vacuo, to provide cis 1-amino-2-indanol.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl>[Br:35][C:3]1[N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: Cc1cccc(-c2ccc3ncc(C(C)c4ccc5nccn5c4)n3n2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cccc(-c2ccc3ncc(C(C)c4ccc5ncc(Br)n5c4)n3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-3-(1-Imidazo[1,2-a]pyridin-6-yl-ethyl)-6-m-tolyl-imidazo[1,2-b]pyridazine (Example 308, 100 mg, 0.283 mmol) was dissolved in DCM (2.8 mL) and NBS (50.4 mg, 0.283 mmol) was added. It was stirred at rt for 1 h then the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated. The residue was repurified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford the title compound after evaporation of the solvent as a white solid. (tR 1.0 min (conditions 2), MH+=432).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=O)[CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCCNC2C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CCCNC3C2)cc1

Procedure:
44 g (about 0.18 mol) of crude or pure 6-benzyl-5,7-dioxo-octahydropyrrolo[3,4-b ]pyridine are reduced with 15.2 g (0.40 mol ) of lithium aluminum hydride in 390 ml of absolute tetrahydrofuran in the course of 10 hours in accordance with the working instructions of Example Ic. 4.4 g of a colorless oil having a boiling point of 93°-95° C./0.06 mbar are obtained on distillation.
Reaction SMILES: [OH-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Cl.[CH3:13]O>>[CH3:13][C:4]1[NH:3][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: CO
Reactant: c1ccc2[nH]cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methanol (2 ml) and a 10% aqueous solution of sodium hydroxide (0.2 ml) were added to optically active 6-(2-benzoyloxy-1-pentane)sulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methyl-benzimidazole isomer with shorter retention time as obtained in Production Example 34 (277 mg) and the mixture was stirred for 90 minutes at room temperature. A 10% aqueous solution of sodium hydroxide (0.36 ml) was further added thereto and stirring was continued for 50 minutes under heating at 50° C. The solution was allowed to cool for 70 minutes to room temperature and 1N hydrochloric acid (1.4 ml) was added thereto and the resulting solution was cooled with ice. Deposited crystals were collected by filtration, washed three times with water (2 ml) and twice with chloroform (1ml), and dried by heating under reduced pressure to obtain optically active 1-(2,4-dichlorobenzyl)-6(2-hydroxy-1-pentane)sulfonyl-carbamoyl)-2-methylbenzimidazole with longer retention time on CHIRALPAK AD (79) (143 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:17][C:2]([F:16])([F:1])[S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:12]#[N:13])[C:10]#[N:11])=[CH:14][CH:15]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(SC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(SC(F)(F)F)cc1
Yield: 4.4 %

Procedure:
Using 0.50 g of (4-(trifluoromethylthio)benzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.09 g of sodium hydride (60% in oil), and 0.38 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.03 g of 2-(4-(trifluoromethylthio)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (13)).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:15]2[CH2:14][O:13]1.[OH-].[Na+]>>[C:1]1([CH2:7][C:8]([N:18]2[CH2:19][CH:15]3[CH2:14][O:13][CH2:12][CH:16]3[CH2:17]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C1NCC2COCC12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cc1ccccc1)N1CC2COCC2C1
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
Phenylacetyl chloride (15.46 grams, 0.1 mole), Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, was slowly added to a mixture of hexahydro-1H-furo(3,4-c)pyrrole hydrochloride (14.96 grams, 0.1 mole) and 300 ml aqueous sodium hydroxide (10.0 grams, 0.25 mole NaOH in water) at 10°C. After the phenylacetyl chloride addition, the ice bath was removed and the reaction mixture was stirred for 1.5 hours. The reaction mixture was extracted with diethyl ether (4 × 200 ml) and the extract treated with DARCO G-60 (activated carbon). Removal of diethyl ether gave 5-phenylacetyl-hexahydro-1H-furo(3,4-c)pyrrole (19.35 grams) a clear viscous liquid which solidified on cooling. This product was recrystallized from diethyl ether and had a melting point of 47.5° to 48.5°C.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]2[S:8][C:9]3([S:23][C:6]=2[CH:5]=1)[CH2:14][CH2:13][N:12](C(=O)C1C=CC=CC=1)[CH2:11][CH2:10]3)([O-:3])=[O:2].[OH-].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]2[S:8][C:9]3([S:23][C:6]=2[CH:5]=1)[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)N1CCC2(CC1)Sc1ccc([N+](=O)[O-])cc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)SC1(CCNCC1)S2
Temperature: 70 °C

Procedure:
1.20 grams of the nitro dithioacetal from Step B in 46 mL of ethanol was treated with 18 mL of 40% aqueous NaOH and heated to 70° C. for 8 hours. The solution was diluted with water and extracted with CH2Cl2. The organics were combined, washed with water, saturated aqueous sodium carbonate, brine, dried (Na2SO4) and concentrated to an oil. The oil was filtered through silica gel eluting with 10% CH3OH in CH2Cl2 to give the product as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1C=CC=CC=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33]>Cl.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.[Cu](I)I>[OH:34][CH2:31][C:32]#[C:33][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1ccccc1)c1cccc(Br)c1
Reactant: C#CCO
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1)c1cccc(C#CCO)c1
Yield: 64.2 %

Procedure:
A mixture of 3-bromo-N-phenyl-benzenesulfonamide (52a) (1.0 g, 3.2 mmol), benzene (2.4 ml), tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.34 mmol), copper iodide (0.032 g, 0.16 mmol), triethylamine (2.4 ml, 17.2 mmol), and propargyl alcohol (1.0 ml, 17.2 mmol)) was refluxed under argon for 30 min. The reaction mixture was diluted with 5% HCl (50 ml) and product was extracted with ethyl acetate (50 ml). The extract was washed successively with 5% NaHCO3, water and dried (Na2SO4). The solvents were removed under reduced pressure and the product was purified on silica gel with ethyl acetate-hexane (1:1, v/v) as eluent. The title compound (0.59 g, 64%) was obtained as an oil. 1H NMR (DMSO-d6, HMDSO) δ: 4.29 (2H, d, J=6.0 Hz, CH2); 5.36 (1H, t, J=6.0 Hz, OH); 6.94-7.32 (5H, m, C6H5); 7.35-7.91 (4H, m, C6H4); 10.32 (1H, s, NH).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:15]([CH3:21])[C:14]2=[O:22])=[CH:8][C:4]=1[C:5](O)=[O:6])#[N:2].S(Cl)([Cl:25])=O>CN(C)C=O>[C:1]([C:3]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:15]([CH3:21])[C:14]2=[O:22])=[CH:8][C:4]=1[C:5]([Cl:25])=[O:6])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(=O)n(-c2cc(C(=O)O)c(C#N)cc2F)c(=O)n1C
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2cc(C(=O)Cl)c(C#N)cc2F)c(=O)n1C

Procedure:
A mixture of 3.0 g of finely pulverised 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid, 30 ml of freshly distilled thionyl chloride and 3 drops of dimethylformamide is heated at reflux temperature for 1 hour with stirring, after which a clear solution has formed. The mixture is then concentrated to dryness by evaporation to yield 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid chloride, m.p. 160° C., which is used, unpurified, as the starting material in the next reaction step.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:9](O)[N:8]=[N:7][C:5]=2[CH:6]=1.CN([P+]([O:21]N1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>>[OH:21][C:6]1[C:5]2[N:7]=[N:8][NH:9][C:4]=2[CH:3]=[CH:2][CH:1]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: On1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Product: Oc1cccc2[nH]nnc12

Procedure:
Competition experiments demonstrate that under the reaction conditions followed the BOP Reagent functions to form the symmetrical acid anhydride within about one minute. During the remaining ten minutes of preactivation mixing a portion of the symmetrical anhydride is converted by HOBt liberated from the BOP Reagent to form an intermediate hydroxybenzotriazole active ester. This active ester intermediate then couples with the available reactive functionalities on the synthesis resin or the coupled amino acid in the peptide chain.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[CH:27]1([C:2]2[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([NH:10][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=3)[CH3:12])=[O:9])=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: C[C@@H](NC(=O)COc1ccc(Br)cc1)c1ccc(OCC(F)(F)F)cn1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)COc1ccc(C2CC2)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 120 °C
Yield: 7 %

Procedure:
To a solution of (R)-2-(4-bromophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide (100 mg, 0.23 mmol) and cyclopropylboronic acid (26 mg, 0.30 mmol) in dioxane (2 mL) were added 1.27 M potassium phosphate (0.36 mL) and tetrakistriphenyl phosphine palladium (13 mg, 0.012 mmol) at room temperature. The mixture was stirred at 120° C. using microwave oven for 2 hours. The mixture was dried over magnesium sulfate. After the filtration to separate solvent and magnesium sulfate, the solvent was removed under reduced pressure to give the residue. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated in vacuo. The residue was purified by preparative LC-MS to give 6.5 mg, (7% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:21].CS([C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[N:27]2[N:26]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:21][C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[N:27]2[N:26]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-c3cccnc3)n2n1
Temperature: 130 °C
Yield: 33.1 %

Procedure:
Into a 8-dram vial, 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (40.0 mg, 0.137 mmol), 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (80.9 mg, 0.313 mmol), Cesium fluoride (41.7 mg, 0.274 mmol), tert-Butyl alcohol (0.80 mL) and N,N-Diisopropylethylamine (0.0478 mL, 0.274 mmol) were added. The reaction mixture was heated at 130° C. overnight. HPLC suggested little if any SM. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a [2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine yellow solid (22 mg, 33%). LCMS (E/I+) 486.18 (M+H). NMR 1H (DMSO-d6)-9.35 (s, 1H), 8.97 (s, 1H), 8.65 (d, 1H, J=8.50 Hz), 8.55 (s, 1H), 7.97 (s, 1H), 7.69 (d, 1H, J=8.50 Hz), 7.50 (t, 1H, J=5.95 Hz), 7.31 (d, 1H, J=4.25 Hz), 6.97 (d, 1H, J=4.25 Hz), 6.73 (s, 1H), 6.58 (d, 1H, J=9.35 Hz), 4.05 (d, 2H, J=11.87 Hz), 3.91 (d, 2H, J=11.87 Hz), 3.83 (s. 3H), 3.67 (t, 2H, J=11.87 Hz), 3.52 (d, 2H, J=11.87 Hz), 3.13 (d, 2H, J=11.87 Hz), 2.73 (t, 2H, J=11.87 Hz), 2.16 (d, 2H, J=11.87 Hz), 1.71 (q, 2H, J=11.87 Hz).