Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)(=O)C.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(O)C>[CH3:21][N:22]1[CH2:27][CH2:26][C:25]2([C:16]3=[C:15]4[C:10](=[N:9][C:8]3=[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]3)[NH:1]2)[CH:11]=[CH:12][CH:13]=[CH:14]4)[CH2:24][CH2:23]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12
Yield: 35.6 %

Procedure:
To a solution prepared from 8 g of 2-(2-aminophenyl)indole, 2.5 ml of acetic acid and 100 ml of ethanol was added 5.15 g of 1-methyl-4-piperidone. The mixture was refluxed for 6 hours. Concentration gave a gum which was triturated with dilute NH4OH and the resultant solid was collected. Flash chromatography using 10% CH3OH/CH2Cl2 as an eluent gave 4.15 g of yellow solid, m.p. 228°-230° dec.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14][NH:15][CH3:16].C1COCC1>C(Cl)Cl>[CH3:14][N:15]([CH3:16])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CNC
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of 3-(chlorosulfonyl)benzoic acid (152 mg, 0.689 mmol) in methylene chloride (2 mL) was treated with 2.0 M dimethylamine in THF (1.137 mL, 2.274 mmol), and the mixture was stirred overnight at room temperature. The reaction was quenched with 1 N HCl, and extracted 3× with EtOAc. The combined organic phases were washed with 1 N HCl followed by brine, then dried over sodium sulfate and concentrated in-vacuo to yield the title compound (138 mg, 0.602 mmol, 87% yield). MS (ESI+)=230.18, (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:28](OC(=O)C)(=O)[CH3:29]>CC1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:1]=[C:28]3[CH3:29])[CH2:14][CH2:13]2)=[O:23])=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: Cc1ccccc1
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 69 %

Procedure:
A mixture of 6 parts of 2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide, 10 parts of acetic acid anhydride and 108 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the oily residue. The whole is alkalized with a dilute sodium hydroxide solution and extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and recrystallized from 2-propanol, yielding 4.4 parts (69%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4(3H)-quinazolinone; mp. 164.9° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH2:10](OC(OCC)OCC)C>C(O)=O>[Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:10]=[N:9][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Br)nc1N
Solvent: O=CO
Product: Brc1ccc2nc[nH]c2n1
Temperature: 100 °C
Yield: 18 %

Procedure:
A stirred mixture of 6-bromopyridine-2,3-diamine (1.30 g, 6.91 mmol) from Step 1 of this Example, formic acid (0.7 mL), and triethylorthoformate (28 mL) was heated at 100° C. for 1.5 h. After the reaction mixture was cooled to rt, the mixture was concentrated under reduced pressure. The residue was triturated with a mixture of 5% MeOH in DCM. The solid was collected by filtration and dried to afford 5-bromo-3H-imidazo[4,5-b]pyridine (245 mg, 18%) as a tan solid which did not require further purification. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluting with 100% DCM to 10% MeOH in DCM) to afford additional 5-bromo-3H-imidazo[4,5-b]pyridine (756 mg, 55%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 13.08 (br s, 1H), 8.50 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H). LCMS (ESI) m/z 198 and 200 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O.Cl.[OH-].[Na+]>O.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCC(=Cc1ccc(OC)c(OC)c1)C2=O
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
6-Methoxy-1-tetralone (7.04 g, 40 mmol) and 3,4-dimethoxybenzaldehyde (6.44 g, 40 mmol) are mixed with 100 ml of absolute ethanol. The mixture is stirred for 0.5 h to dissolve as much as possible of the reagents. The introduction of gaseous hydrogen chloride is commenced. An exothermic reaction is noted which enables the complete dissolution of all of the reagents. The round-bottomed flask is cooled from time to time with an ice bath so that the temperature does not exceed 80° C. The mixture is thus saturated with hydrogen chloride after 1 h to give an intense red color. This mixture is allowed to stand at room temperature for 2 h. The reaction mixture is poured into a mixture of 400 ml of water and 40 ml of aqueous NaOH (3N). It is stirred vigorously for 3 h at room temperature. The precipitated solid is filtered over a glass frit, washed with water and finally dried under vacuum, over P2O5, to give a solid (12.35 g, 95%). A small quantity of product is recrystallized from the mixture AcOEt/hexane=1:2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>C(O)(C)C>[ClH:36].[F:33][CH:31]([F:32])[O:30][C:26]1[CH:25]=[C:24]([S:21]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([O:34][CH3:35])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1

Procedure:
0.17 g of 4-[5-(3-Difluoromethoxy-benzenesulfonylamino)-2-methoxy-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.331 mmol) from preparation example 1 were treated with 1 ml of 5 N HCl in isopropanol for 3 h at 35° C. The solvent was evaporated and 5 mL of diethyl ether were added. The product started to crystallize upon scratching the glass surface. The solvent was evaporated and the solid dried thoroughly at room temperature to yield 0.125 g of title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:42])[C:25]([CH3:41])([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)[CH3:26]>>[CH3:22][O:23][C:24](=[O:42])[C:25]([N:27]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:10]([C@@H:11]([C:13]4[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=4[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:29]=[N:28]1)([CH3:41])[CH3:26]
Reactant: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Product: COC(=O)C(C)(C)n1cc(-c2cnc3[nH]cc([C@H](C)c4c(Cl)ccc(F)c4Cl)c3c2)cn1

Procedure:
The 2-(4-{3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-2-methylpropionic acid methyl ester was prepared from 5-bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine and 2-methyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]propionic acid methyl ester as described in Example 60.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:13]=[C:12]([CH3:22])[CH:11]=1)(=O)C.Cl>CO>[ClH:21].[Cl:21][C:17]1[CH:16]=[C:15]([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][C:12]([CH3:22])=[N:13]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2cccc(Cl)c2)n1

Procedure:
1-Acetyl-2-[1-(3-chlorophenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (19.7 g.) was treated with HCl in methanol as described in Example II to give 6.5 g. product as the HCl salt, mp 208°-209°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[I:14]([O-])(=O)=O.[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[I:14][C:10]1[C:11]([NH2:13])=[CH:12][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][CH:9]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: Nc1ccnc(C2CCOCC2)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: Nc1cc(C2CCOCC2)ncc1I
Reaction time: 2.5 h
Yield: 27.1 %

Procedure:
To a stirred solution of 5.80 g (32.5 mmol) 2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine in 20 ml 65% aqueous sulfuric acid heated to 135° C. was added 7.66 g (35.8 mmol) potassium iodate and stirring continued for 2.5 h at 135° C. The mixture was then cooled in an ice-bath before being made basic by addition of 5 N aqueous sodium hydroxide solution. The mixture was extracted three times with tetrahydrofuran and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was resuspended in 200 ml tetrahydrofuran and 200 ml ethyl acetate and then concentrated in vacuo to 70 ml. The resulting crystals were collected by filtration to afford 2.68 g (27%) 5-iodo-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine as a white crystalline solid. ES-MS m/e (%): 305 (M+H+, 100). The mother liquor was concentrated in vacuo; flash chromatography (methanol/dichloromethane 1/50 to 1/20) afforded a further 0.79 g (8%) 5-iodo-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine as a white crystalline solid, as well as 0.98 g (10%) 3-iodo-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine as a white crystalline solid. ES-MS m/e (%): 305 (M+H+, 100).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C1C=CC2S(=O)(=O)OC(C3C=C(Br)C(O)=C(Br)C=3)(C3C=C(Br)C(O)=C(Br)C=3)C=2C=1.Cl.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].[OH-].[Na+]>CCOCC.CO.O>[NH2:3][CH2:2][CH2:1][NH:4][C:36](=[O:37])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=S1(=O)OC(c2cc(Br)c(O)c(Br)c2)(c2cc(Br)c(O)c(Br)c2)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A mixture of ethylenediamine (60 g, 1 mole), water (250 ml), methanol (500 ml) and Bromophenol Blue solution was acidified to pH 3 (yellow color) with hydrochloric acid (165 ml, 12 N). While the resulting solution was vigorously stirred at 25° C., benzyl chloroformate (100.6 g, 0.59 mole) was added dropwise (addition time 1.75 hours). Sodium hydroxide (210 ml, 5 N) was added as required to maintain the solution at pH 3.0-4.5. The methanol was removed at reduced pressure and the reaction mixture was filtered. The aqueous filtrate was extracted once with benzene, and the benzene extract was discarded. The aqueous solution was cooled in a salt-ice bath, layered with ether and treated with sodium hydroxide (130 ml, 10 N) to pH 11-13. Three layers formed: an ether layer, an aqueous layer, and an oily blue layer. The aqueous layer was separated and extracted four times with portions of ether. The ether layer and ether extracts were combined with the oily blue layer and the ether removed using water pump vacuum. An oil pump was then used at 25° C. until the pressure dropped to 0.6 ppm. During this time, water and ethylenediamine were removed by distillation. The residue left in the flask consisted of an oil and a small amount of solid. After the mixture was filtered, 60 g (54% yield) of benzyl N-(2-aminoethyl)carbamate were obtained. This crude oil worked satisfactorily in the next step without further purification. See C. M. Hoffmann and S. R. Sapir, Journal of Organic Chemistry, 27, 3565 (1962) for further discussion of this preparatory method.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[P:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:30]1([PH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: CCCCc1ccc(S(N)(=O)=O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Commercially available 4-butylbenzene-1-sulfonamide (9.376 mole, 1 eq) was dissolved in tetrahydrofuran (20 mL) and triethylamine (25 mmole), leading to a clear colorless solution. Distilled chlorobisphenylphosphine (9.376 mmole, 1.0 eq) was added dropwise under strong magnetic stirring at room temperature. The suspension was left to stir overnight at room temperature. The suspension was then filtered under argon atmosphere and the resulting clear solution was evaporated to a white solid. The product was redissolved in 10 mL of diethylether leading to a clear solution. 10 mL of pentane were added dropwise to the solution causing a white solid to crash out. The organic layer was syringed out, and the white solid obtained was washed twice with 10 mL of pentane. The product was filtered over a short silica gel column with dichloromethane as eluent. The product was obtained as white solid. The product was characterized by 1H, 31P, 13C NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([CH3:38])[CH:30]=2)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:27]=[C:26]([O:28][C:29]5[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([CH3:38])[CH:30]=5)[N:25]=[CH:24][N:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc([N+](=O)[O-])c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
0.69 g (2.51 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.66 g (2.48 mmol) 4-chloro-6-(3-methyl-4-nitrophenoxy)pyrimidine and 1.0 mL (5.81 mmol) DIPEA in 1.0 mL DMF were stirred overnight at 40° C. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[NH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:29][C:30]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[O:32][N:31]=1>C(#N)C>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]2[CH2:29][C:30]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:42])[F:43])[CH:36]=2)[O:32][N:31]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Yield: 14.7 %

Procedure:
To a solution of 4-(trifluoromethyl)-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile (Example 302A) (0.200 g, 0.653 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (0.851 g, 2.612 mmol) and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.257 g, 0.979 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.051 g, 24% yield): MS (ES) m/z 532 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)=O.CO.[Pd].C(OCC)(=O)C.C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH2:16])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)[C@H](N)Cc1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (310 mg) in 4.4% formic acid in methanol (20 ml, freshly prepared in degassed methanol) was added via cannula to a suspension of 10% palladium on charcoal in 4.4% formic acid in methanol (20 ml, freshly prepared in degassed methanol). The resulting mixture was stirred at room temperature for 4 h. After filtration through a pad of celite, the solvents were removed in vacuo giving a tan solid. The solid was dissolved in a mixture of ethyl acetate (50 mL), toluene (10 mL) and ethanol (40 ml), and solid sodium bicarbonate (3.1 g) was added. The mixture was stirred at room temperature for 2 h and filtered. Solvents were removed in vacuo to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(O[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)Oc1ccccc1
Product: O=C(Oc1ccccc1)c1ccc(O)cc1
Temperature: 180 °C

Procedure:
828 g. (6 moles) of p-hydroxybenzoic acid and 1020 g. (6.5 moles) of phenyl acetate are charged into a four-necked resin kettle equipped as in Example 3. The reaction mixture is stirred constantly under a nitrogen atmosphere throughout the run. The reaction mixture is heated to 180°C, and gaseous HCl is then bubbled through the mixture for 7 hours, the temperature being held at 180°C. Phenyl p-hydroxybenzoate is produced thereby. The HCl flow is discontinued and 660 g. (6 moles) of hydroquinone is added to the charge. The distilling head is heated to 180°C, and the reaction mixture is heated from 180°C to 230°C at a rate of 10°C/hour, held for 4.5 hours at 230+C, and heated to 240°C where the temperature is held for 2 hours. The resulting pasty melt is poured while hot into a tray and allowed to cool and solidify, whereupon it is pulverized. A yield of 1413 g. is obtained. The product consists primarily of an ester, p-hydroxyphenyl p-hydroxybenzoate, having Formula XVII wherein R4 and R9 are each hydrogen, n is 0, and the dioxyarylene moiety is para-dioxyphenylene. The product also contains a linear polyester identical to that produced in Example 6. The desired ester is separable from the linear polyester by virtue of its greater solubility in such solvents as acetone. Accordingly, the product is extracted with hot acetone to obtain a solution of the ester and water is added to the solution to precipitate the ester, which is removed by filtration, dried in vacuum, and crystallized from aqueous isopropyl alcohol. The ester is found to have a melting point of 243°C upon differential thermal analysis.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.[CH3:13][C:14]1[N:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([C:25]#[N:26])[C:18](=[O:24])[NH:19]2>O>[CH3:13][C:14]1[N:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([C:25](=[N:2][OH:3])[NH2:26])[C:18](=[O:24])[NH:19]2
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nccc2[nH]c(=O)c(C(N)=NO)cc12
Yield: 96.3 %

Procedure:
To a solution of hydroxylamine hydrochloride (4.17 g) in water (50 ml) was added sodium carbonate (3.18 g) with stirring under ice cooling. To the solution were subsequently added ethanol (200 ml) and 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile (3.70 g), and the mixture was refluxed for 2 hours. After distilling off the solvent under reduced pressure, water was added to the residue, and the precipitated crystals were separated by filtration. The product was washed with water, isopropanol, diisopropyl ether in this order, and dried to give 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridin-3-amidoxime (4.2 g). This compound was used in the next reaction without being purified.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(C(F)(F)F)=O>[C:11]([S:4][CH2:3][CH2:2][NH2:1])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCS
Solvent: O=C(O)C(F)(F)F
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cysteamine (commercial) (900 mg, 11.67 mmol) was added to a stirred solution of triphenylmethanol (commercial) (3.037 g, 11.67 mmol) in TFA (10 ml) and the mixture stirred at RT for 3 hours. The mixture was then concentrated under reduced pressure and the residue partitioned between DCM (20 mL) and water (20 mL). The mixture was basified by the slow addition of solid K2CO3. The aqueous phase was extracted with DCM (2×20 mL), the combined organic phases passed through a hydrophobic frit and the solvent evaporated under reduced pressure. The material was used without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[N:8][CH:9]=1.I[CH3:15].O>CN(C)C=O>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]([O:13][CH3:15])([CH3:11])[CH3:12])[CH:5]=1
Reactant: CI
Reactant: CC(C)(O)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 46 mg, 1.2 mmol) in N,N-dimethylformamide (4.6 mL) at 0° C. was added a solution of the title compound from Example 22 Step C (100 mg, 0.463 mmol) in N,N-dimethylformamide (4.6 mL). After warming to room temperature and stirring for 1 hour, the solution was cooled back to 0° C. and iodomethane (35 μl, 0.56 mmol) was added. After stirring overnight, the reaction was poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound: LCMS m/z 232.97 [M+H]+.