Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([CH2:15][CH3:16])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:15]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([N:1]3[CH:21]=[CH:25][CH:24]=[CH:23]3)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:6](=[O:18])[C:7]1=[O:17])[CH3:16]
Reactant: COC1CCC(OC)O1
Reactant: CCn1c(=O)c(=O)[nH]c2cc(N)c([N+](=O)[O-])cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCn1c(=O)c(=O)[nH]c2cc(-n3cccc3)c([N+](=O)[O-])cc21
Yield: 374.7 %

Procedure:
4.0 g (16 mmol) of 6-amino-1-ethyl-7-nitro-2,3(1H,4H)-quinoxalinedione, 2.4 g (18 mmol) of 2,5-dimethoxytetrahydrofuran and a spatula tip of p-toluenesulfonic acid were refluxed in a mixture of 50 ml of dimethylformamide and 50 ml of toluene with a water trap for 3 h. The mixture was then concentrated under reduced pressure, and the residue was treated with methanol. The precipitate was filtered off with suction to yield 18 g (3%) of the product.
Reaction SMILES: C([O:4][C:5](=[O:24])[CH:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])(C)C.[Li+].[OH-]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:5]([OH:24])=[O:4])=[CH:13][C:14]=1[C:20]([F:21])([F:23])[F:22])#[N:19]
Reactant: CC(C)CC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C

Procedure:
An admixture of 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid isopropyl ester (1A) (0.22 g, 0.67 mmol in 20 ml of dry tetrahydrofuran “THF”), LiOH (0.28 g, 6.7 mmol) and water (20 ml) is refluxed at 100° C. for 3 hours, then it is cooled to room temperature, the THF is removed, the crude product is diluted with 100 ml of ethyl acetate, and HCl(1N) to adjusted PH=1. The organic layer is separated and dried on vacuum to get the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[C:9]2([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[N+:20]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:20][C:3]1[CH:4]=[C:5]([CH:8]([OH:19])[C:9]2([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(N)c2)CC1
Reaction time: 72 h

Procedure:
2.72 g (8.30 mmol) of tert-butyl 1-[(4-chloro-3-nitrophenyl)(hydroxy)methyl]cyclopropane-carboxylate were dissolved in 100 ml of ethyl acetate, and 177 mg of palladium on carbon (10%) were added. For three days, the reaction mixture was stirred vigorously under a stationary atmosphere of hydrogen at atmospheric pressure. The mixture was then filtered through Celite and the filtrate obtained was evaporated to dryness. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 1.97 g of the target compound (80% of theory).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 135.9 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (48 g) and 2-(4-fluorophenyl)ethyl p-toluenesulfonate (38 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (65 g), melting point 114-116° C. The obtained free basic compound (65 g) was dissolved in ethyl acetate, and 20% hydrochloric acid-isopropanol solution (35 g) was added thereto. After cooling, the precipitated crystals were collected by filtration to yield 57.4 g of crystals. The filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue. After cooling, the precipitated crystals were collected by filtration to yield 10.9 g of crystals. The obtained crystals were combined and recrystallized from a mixed solvent of ethanol (400 mL) and water (1500 mL) using activated carbon to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide hydrochloride monohydrate (54 g), melting point 201-204° C.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Br:13])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:27][CH2:28][C@H:29]([OH:31])[CH3:30]>C1(C)C=CC=CC=1>[Br:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:27]([CH2:28][C@H:29]([OH:31])[CH3:30])[C:5]=32)=[CH:10][CH:9]=1
Reactant: O=CCC1Cc2ccc(Br)cc2C1=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1ccc2c1-c1cc(Br)ccc1C2
Reaction time: 0.75 h
Yield: 51.5 %

Procedure:
A solution of 2.0 g of (RS)-2-(2-oxoethyl)-6-bromo-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.37 g of (R)-1-amino-2-propanol in 10 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 4:1). 1.19 g (52%) of (R)-1-(7-bromo-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1]([C:3]([CH3:11])=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[O-])#[N:2].[K+].CCO.Cl.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18]>CCOC(C)=O.O>[CH2:9]([O:8][C:6]([C:4]1[C:3]([CH3:11])=[C:1]([NH2:2])[N:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:22]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C([O-])=C(C)C#N
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nn(C(C)(C)C)c(N)c1C

Procedure:
Placed 47 (1.0 eq.) into a sealed pressure reaction flask. Added EtOH and t-butylhydrazine hydrochloride (1.1 eq.). The pressure flask was capped and heated to reflux. After a time sufficient for reaction completion, the mixture was evaporated to dryness and the solid obtained was dissolved in equal amounts of EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, brine, dried with MgSO4, and evaporated. This slightly yellow solid was triturated with hexanes and filtered to afford ester 48.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29]([OH:31])=O)=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29]([NH:35][CH2:34][CH2:32][OH:33])=[O:31])=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1
Reactant: NCCO
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)n(-c2ccc(F)cc2F)n1
Product: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)NCCO)cc2OCC3)n(-c2ccc(F)cc2F)n1

Procedure:
Similarly to as described in General Procedure D, 2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid was reacted with ethanolamine to give 151 as a colorless solid after reverse phase HPLC (85 mg). LCMS: 484.1
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:27]1[CH:28]=[CH:29][CH:30]=[N:31][C:26]=1[N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1
Reactant: Clc1ncccn1
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccccc2)CCN(c2ncccn2)CC1
Yield: 47 %

Procedure:
To a mixture of 4.0 gms (0.017 mole) 4-phenyl-4-carboethoxy-piperidine and 1.72 gms (0.017 mole) of triethylamine in 50 ml. toluene was added dropwise 2.0 gms (0.017 mole) 2-chloropyrimidine. Triethylamine hydrochloride started to precipitate out almost immediately. The reaction mixture was warmed to 70°-80° for a period of two hours, and then allowed to cool. The triethylamine hydrochloride was filtered off and the filtrate washed with water (to remove the last traces of triethylamine hydrochloride). The residue was recrystallized from acetone to yield 2.5 gms (47% yield), m.p. 119°-120°.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([F:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc(F)c3)c2cn1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of 7-amino-4 -methylthiopyrido[4,3-d]pyrimidine (215 mg, 1.12 mmol) and 3-fluoroaniline (1.16 g, 10.4 mmol) is stirred at 160° C. for 30 min. The resulting product is chromatographed over silica gel (6-7% MeOH/CH2Cl2) to give 7-amino-4-(3-fluoroanilino)pyrido[4,3-d]pyrimidine (185 mg, 65%) as a white solid. 1H NMR (DMSO) δ 9.94 (1H, brs), 9.36 (1H, s), 8.46 (1H, s), 7.91 (1H, brd, J=11.9 Hz), 7.63 (1H, brd, J=8.1 Hz), 7.41 (1H, dd, J=15.7, 7.7 Hz), 6.93 (1H, dt, Jt =8.5 Hz, J =2.4 Hz), 6.68 (2H, brs), 6.38 (1H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.O.[Cl-].[Na+]>[C:25]([NH:29][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)NC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
To a cooled to −30° C. solution of indole-5-carboxylic acid and triethylamine in DMF was added methyl sulfonyl chloride in portions to avoid temperature elevation. Following the addition, solution was warmed to room temperature and was stirred for 1 hour and 15 minutes. Reaction mixture was then cooled to −20° C. and N-tert-butyl-amine was added in two portions so the temperature remained at −10° C. After 13 hours of stirring, the solution was diluted with water and saturated with sodium chloride. The solution was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound as a thick brown oil (NMR showed 34% DMF) (28% yield), melting point=176.4° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[C:8]#[CH:9].[F:11][C:12]1[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].[K+].[Br-]>CC(C)=O.O.C(N(CC)CC)C>[CH2:7]([NH:10][C:16]1[CH:17]=[C:12]([F:11])[C:13]([N+:22]([O-:24])=[O:23])=[CH:14][C:15]=1[N+:19]([O-:21])=[O:20])[C:8]#[CH:9]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: C#CCNc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of potassium carbonate (6.0 g) in acetone (25 ml) was added triethylamine (1.5 ml) and 2-propyn-1-amine (2.35 g, 4.25×10-2 mole). 1,5-Difluoro-2,4-dinitrobenzene (10.00 g, 4.90×10-2 mole) was added and the reaction mixture was stirred at room temperature for 24 hours. The mixture was poured into excess water and filtered. The resulting dark solid was chromatographed on a silica column, eluting with benzene, and recrystallized from benzene to afford yellow crystals; m.p. 113°-115° C. Yield: 8.33 g (82%). I.R. (KBr): 3340 (NH), 3280 (CH), 1615, 1260 (Ar-NO2) and 1210 cm-1 (Ar-F).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.[C:36]1([S:42]([OH:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Na]>CN(C)C=O>[C:36]1([S:42]([CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]2[C:20]3[CH2:19][N:18]4[C:13](=[CH:14][C:15]5[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=5[C:17]4=[O:21])[C:12]=3[N:11]=[C:10]3[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=23)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=S(O)c1ccccc1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCS(=O)(=O)c1ccccc1

Procedure:
A slurry of Compound 11 (25 mg) and benzenesulfinic acid, sodium salt (15 mg) in N,N-dimethylformamide (0.5 mL) was heated at 70° C. for 5 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and the residue was directly eluted on a silica gel using 2% ethanol in dichloromethane to obtain the required product in quantitative yield (28 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[N:11][CH:12]=1.[CH3:20][C:21]1([CH3:32])[C:25]([CH3:27])([CH3:26])[O:24][B:23](OC(C)C)[O:22]1>C1COCC1>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([B:23]2[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:32])([CH3:20])[O:22]2)=[CH:12][N:11]=1
Reactant: CN(C)CCCOc1ccc(Br)cn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 18 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
Butyllithium (2.5N, 4.8 mL, 50.96 mmol) was added to a solution of 3-(5-bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2.07 g, 7.99 mmol) and 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (2.79 g, 15.00 mmol) in THF (20 mL) at −78° C. over 10 minutes under an inert atmosphere. The resulting solution was stirred for 4 h at 18° C. The reaction was then quenched by the addition of a sat. aqueous solution of ammonium chloride then partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was concentrated in vacuo and the residue purified by FCC, eluting with EtOAc/petroleum ether (1:3) to afford the desired material (270 mg, 11%) as a yellow solid. Mass Spectrum: m/z (ES+)[M+H]+=225.
Reaction SMILES: [Br:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][CH:7]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][C@H:9]([OH:26])[C@@H:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CO[C:49](OC)([CH3:51])[CH3:50]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C@H:10]1[C@H:9]([CH2:8][CH:7]([NH:27][C:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[CH2:6][C:5]2[CH:38]=[CH:39][C:2]([Br:1])=[CH:3][CH:4]=2)[O:26][C:49]([CH3:51])([CH3:50])[N:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CC(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccccc2)[C@H](CC(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution containing the product from Example 128A (3.37 mmol) in 2,2-dimethoxypropane (35 mL) was treated with p-toluenesulfonic acid monohydrate (0.032 g, 0.17 mmol), stirred at 25° C. for 1 hour, treated with triethylamine (0.14 mL, 1.0 mmol), and the reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the product (1.16 g, 54% yield), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.O.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([N:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([OH:11])=[N:5]1)=[O:15])[CH3:18]
Reactant: Oc1n[nH]c2cccc(Br)c12
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1nc(O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature suspension of 4-Bromo-1H-indazol-3-ol CLXXXIII (3.19 g, 15.0 mmol) in pyridine (13 ml) and H2O (20 ml) was dropwise added ethyl chloroformate (1.43 ml, 15.0 mmol). After stirring 18 hours at room temperature, the mixture was cooled to 0° C., and the precipitate was filtered and washed with cold AcOH (10 ml in 5 ml of H2O). The solid was dried in vacuo affording 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV as a yellow powder (2.97 g, 69% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>CO.C(Cl)Cl>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1F
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CNc3ccccc3F)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 2-fluoroaniline (55 mg, 0.50 mmol) as described in General Procedure X to afford Iai (12 mg, 18.2%) as an ivory colored solid, tlc Rf=0.8 (5% MeOH/CH2Cl2−0.2% Et3N), m/z obs=392 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O>O.O1CCCC1>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1/[CH:21]=[CH:9]/[C:7]#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#C/C=C/c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
To a solution of 8 g of potassium carbonate in 10 cm3 of water, 6 g (0.034 mol) of diethyl cyanomethylphosphonate are added followed by 5 g of 2,4-dichlorobenzaldehyde solubilized in 10 cm3 of anhydrous tetrahydrofuran. The mixture is left stirred for 10 minutes at room temperature and 20 cm3 of water are added. The precipitate formed is washed with water to neutrality (8 times with 20 cm3 of water), and then washed with an ether/hexane mixture. 3.7 g (74%) of trans-2,4-dichlorocinnamonitrile are obtained in the form of white crystals, m.p. 156° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[F:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:47]3[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCCS(=O)(=O)c1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(F)cc2)c1
Yield: 92 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-(propane-1-sulfonyl)-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (220 mg, 0.33 mmol), 4-fluoro-phenylboronic acid (92.1 mg, 0.66 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol), and cesium carbonate (217 mg, 0.66 mmol) to afford 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-1-sulfonyl)-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (208 mg, 92%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C38H49FO8S (M+Na)+ 707.3024, found 707.3023.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3](=[O:23])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][O:21][CH3:22])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:35]1[C:36]2[C:43]([CH3:44])=[CH:42][NH:41][C:37]=2[N:38]=[CH:39][N:40]=1>C(O)(C)C>[CH3:24][N:2]([CH3:1])[C:3](=[O:23])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][O:21][CH3:22])[CH2:15][CH2:16][N:17]([C:35]3[C:36]4[C:43]([CH3:44])=[CH:42][NH:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: COCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 110 °C
Yield: 42 %

Procedure:
To a solution of 3-(4-(methoxymethyl)piperidine-4-carboxamido)phenyl dimethylcarbamate, from step D, and N,N-diisopropylethylamine (2 mL, 11.9 mmol) in isopropanol (5 mL) was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (397 mg, 2.37 mmol). The reaction mixture was heated to 110° C. in a sealed high-pressure vial for 17 hours, during which time the mixture became homogenous. The reaction was concentrated under vacuum and purified by silica gel chromatography (3-5% methanol:CH2Cl2). The product was washed with cold methanol to provide the title compound as an off-white solid (462 mg, 42% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:5]([O:19][Si](C(C)(C)C)(C)C)[CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.C[O:38][C:39](=O)[C@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:39](=[O:38])[C@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2[C:10]1=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:19]
Reactant: COC(=O)[C@H]1CCCN1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(N=C2N(c3ccccc3Br)C(=O)[C@H]3CCCN23)c(O)c1
Yield: 77.8 %

Procedure:
The standard procedure was followed using N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide (107 mg, 0.25 mmol), diisopropylethylamine (71 μL, 0.55 mmol), D-proline methyl ester hydro chloride (46 mg, 0.28 mmol) and TBAF (0.30 mL, 0.30 mmol) in THF (2.5 mL) and methanol (0.1 mL) to give 80 mg (78%) of 4-[[(7aR)-2-(2-bromophenyl)-hexahydro-1-oxo-3H-pyrrolo[1,2-c]imidazol-3-ylidene]amino]-3-hydroxybenzonitrile as a tan powder. MS(EI) m/e 411 (100(M+)).