Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([N:7]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Li]CCCC.C(O[B:42]1[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]1)(C)C>C1COCC1>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([N:7]([C:20]2[CH:25]=[CH:24][C:23]([B:42]3[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]3)=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
N-(biphenyl-4-yl)-N-(4-bromophenyl)biphenyl-4-amine (56 g, 0.117 mol) was introduced into a 2 L RBF, and dissolved in THF (600 ml). Then, the temperature was maintained at −78° C. for about 30 minutes. Then, n-BuLi (1.6M in Hex) (90 ml, 0.141 mol) was slowly added thereto. After 1 hour, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26.2 g, 0.141 mol) was added thereto, followed by heat-stirring at room temperature for 12 hours. After the reaction was completed, the resultant solution was sufficiently washed with distilled water and Brain, and purified through column chromatography to obtain N-(biphenyl-4-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)biphenyl-4-amine (white solid, 20 g, yield 33%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCCC1>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][NH:11][S:12](=[O:14])(=[O:13])[NH2:15])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNS(N)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
According to Reference Example 9-26, tetrahydrofuran (3 mL) and N—BOC-ethylenediamine (0.66 mL, 4.2 mmol) were added to sulfamide (400 mg, 4.2 mmol) and the mixture was stirred by use of a microwave chemical reactor at 300 W at 100° C. for 10 minutes. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=1/0 to 9/1) was performed to give N-[2-(tert-butoxycarbonylamino)ethyl]-sulfuric diamide (Compound GJ) (500 mg, yield: 50%).
Reaction SMILES: ClCCl.[CH3:4][C:5]([NH:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:6][C:5]([N:15]1[CH:16]([CH3:20])[C:17]([CH3:18])=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:29]1=[O:30])([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:4]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: CC(=O)C(C)NC(C)(C)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2ccc(Cl)c(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To 20 ml of dichloromethane were added 3.0 g of N-[1-methyl-1-(3,4-dichlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine and 3.5 g of pyridine, and 4.0 g of 2-fluorophenylacetyl chloride was then added dropwise thereto at 5° to 10° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with dichloromethane. After dried over anhydrous sodium sulfate, the solution was concentrated by an evaporator, and the resulting oil was dissolved in 20 ml of ethyl acetate. Next, 10 ml of a 28% methanol solution of sodium methylate was added thereto, and after stirring under reflux for 15 minutes, the temperature of the solution was returned to room temperature and water was then added, followed by extraction with ethyl acetate. Afterward, the solution was washed with a 12% hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. Next, the solution was concentrated by an evaporator, and then subjected to silica gel chromatography to obtain 2.5 g of 1-[1-methyl-1-(3,4-dichlorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>O>[N:1]1([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a mixture of imidazole (5.13 g, 75.35 mmol) , K2CO3 (11.45 g) and DMSO (50 ml) at room temperature was added to 4-fluorobenzonitrile (10.04 g) in one portion. The reaction mixture was stirred at room temperature for 1 hour, and then was warmed on a steam for 2 hours. The reaction mixture was cooled to room temperature, and poured into cold water. A precipitate formed which was collected by filtration and washed with water and recrystallized from CHCl3 /hexane to afford 4.07 g of 4-(1-imidazolyl)benzonitrile, m.p. 146°-148° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(OC(F)(F)F)c4)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo [1,2-α]pyridin-7-yl]-propan-2-ol and 3-trifluoromethoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-3′-trifluoromethoxybiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (4 mg, 3%): m/z (ES+) 449 [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[Cl:15].Cl.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[ClH:17].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[S:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2cc1OC
Yield: 71 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 16 hours, 4-amino-2-chlorophenyl 1-methylimidazol-2-yl sulphide was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(1-methylimidazol-2-ylthio)anilino]-6,7-dimethoxyquinazoline dihydrochloride salt in 71% yield, m.p. 244°-246° C.;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].CCN(CC)CC.[CH3:39][N:40]=[C:41]=[O:42]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:41](=[O:42])[NH:40][CH3:39])[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
A solution of 3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (145 mg, 0.33 mmol) in CH2Cl2 (3.3 mL) was treated with Et3N (69 mL, 0.49 mmol) and methyl isocyanate (28.2 mg, 0.49 mmol). After stirring at room temperature for 18 h, starting material remained. Methyl isocyanate (28.2 mg, 0.49 mmol) was added to the reaction that was stirred for another 4 h. The solvent was evaporated and the residue was dissolved in EtOAc, washed with HCl (0.1 M) and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (5% MeOH/CH2Cl2) to provide 3-[(1-Methylcarbamoyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (142 mg, 87% yield). 1H NMR (CDCl3, 400 MHz): 7.65 (m, 2H), 7.45 (m, 3H), 7.00 (s, 1H), 4.78 (m, 1H), 4.35 (q, 1H), 4.05 (dd, 1H), 3.90 (m, 1H), 3.85 (s, 3H), 2.85 (m, 2H), 2.75 (d, 3H), 1.95 (m, 2H), 1.80 (m, 1H), 1.70-1.55 (m, 5H), 1.50-1.25 (m, 3H), 1.10 (m, 1H), 0.78 (d, 3H), 0.75-0.58 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[S:9][CH2:8][CH2:7][NH:6][C:5]2=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1.I([O-])(=O)(=O)=[O:16].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[S:9](=[O:16])[CH2:8][CH2:7][NH:6][C:5]2=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1
Reactant: O=C(O)c1cc(Br)cc2c1NCCS2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2c1NCCS2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 7-bromo-3,4-dihydro-2H-1,4-benzothiazine-5carboxylic acid (500 mg) in methanol (80 ml) was added 0.05 M sodium metaperiodate solution (40 ml). The mixture was stirred for 5 hours at room temperature, then diluted with water (500 ml) and concentrated until crystals began to separate. The crystals were collected and dried to give the title compound (300 mg, 57.5% which was recrystallized from ethanol to give pale yellow crystals, mp 254°-255° C. (decompd.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45]C)=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.B(Br)(Br)Br.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:45])=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(F)ccc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 47 %

Procedure:
(S)-2-(1-((5-(5-Fluoro-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (55 mg, 0.09 mmol) was treated with boron tribromide (1 M in dichloromethane, 1 mL, 1 mmol) and a solution of ammonia (7N in methanol, 1 mL, 7 mmol) according to the method described in Example 27 to give 20 mg (47% yield) of the title. Purity 94%.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([F:13])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][C:3]#[N:4])=[C:8]([F:13])[CH:7]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1ccc(Br)cc1F
Reaction time: 12 h

Procedure:
Bromoacetonitrile (1.81 ml, 0.026M) was added to a solution of 4-bromo-2-fluorophenol (5.0 g, 0.026M) and potassium carbonate (3.54 g, 0.026M) in DMF (50 ml). The reaction was stirred for 12 hours and then partitioned between diethyl ether (200 ml) and water (200 ml). The organics were separated, dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a yellow oil (6.0 g). 1H NMR (CDCl3): δ 4.84 (s, 2H), 7.03–7.10 (m, 2H), 7.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:33]=[N+:34]=[N-:35])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2cc(CO)ccc2OC)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cc(CN=[N+]=[N-])ccc2OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
A solution of 4-methoxy-3-(4-methoxyphenyl)benzyl alcohol (0.88 g, 3.59 mmol) and diphenylphosphoryl azide (1.18 g, 4.32 mmol) in anhydrous THF (15 mL) was cooled in an ice-bath prior to addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.87 g, 5.76 mmol). The resulting mixture was then stirred at room temperature for 48 hours. More diphenylphosphoryl azide was added (1.4 mol, 0.39 g) and the mixture stirred for further 16 hours. The solvent was then evaporated, the residue taken into dichloromethane and washed with acid. The organic layer was separated and the solvent removed under reduced pressure to afford 0.82 g of title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[CH:6][N:5]=1.[H][H]>CN(C)C=O.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11](=[O:12])[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[N:5][C:4]2=3)=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2cccnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2c3ncccc3NC(=O)c3cccnc32)cc1
Temperature: 110 °C
Yield: 48.1 %

Procedure:
1.44 g of a 50% dispersion of sodium hydride in mineral oil was added to a solution of 3.69 g (0.010 mol) N-(2-chloro-3-pyridinyl)-2-[[(4-methoxyphenyl)methyl]amino]-3-pyridinecarboxamide in 100 ml of dimethylformamide. After the evolution of hydrogen stopped, the mixture was heated (110° C.) for 16 hours and then refluxed for eight hours. After the mixture had cooled, the excess sodium hydride was decomposed by the slow addition of ice. The mixture was further diluted with water, and the product was extracted with ether and concentrated. The crystallized residue was filtered and washed with ether to give 1.60 g of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (50% of theory) as an off-white powder, m.p. 209°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=[O:22])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[CH3:23][NH2:24].O>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11](=[O:22])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:24]1[CH3:23]
Reactant: CN
Reactant: COc1ccccc1C=CC(=O)C=Cc1ccccc1OC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1C1CC(=O)CC(c2ccccc2OC)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
1,5-Bis(2-methoxyphenyl)-1,4-pentadien-3-one (20c, 0.26 g, 0.9 mmol) was dissolved in dimethyl formamide (5 ml). Methylamine (51, 0.40 ml, 4.6 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 24 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The solid was recrystallized twice from ethanol to give 0.16 g (55%) of a white solid: mp 146-148° C.; 1H NMR δ 1.89 (s, 3H), 2.50 (d, 2H, J=13.7 Hz), 2.65 (t, 2H, J=11.9 Hz), 3.82 (s, 6H), 4.11 (d, 2H, J=11.5 Hz), 6.87 (d, 2H, J=8.3 Hz), 7.03 (t, 2H, J=7.2 Hz), 7.23 (t, 2H, J=5.8 Hz), 7.72 (d, 2H, J=7.6 Hz); 13C NMR: δ 40.3, 49.2, 55.4, 61.2, 110.7, 121.0, 127.6, 127.8, 131.5, 156.3, 208.1; Exact mass calcd for C20H23NO3: 325.1678, observed (M+H) 326.1754.
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][NH2:15].N>>[CH3:14][NH:15][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: CN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: N
Product: CNS(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
The title compound was prepared according to the procedure of Example 50A using 3-(chlorosulfonyl)benzoic acid (Aldrich) and methylamine (Aldrich). 1H NMR (300 MHz, CD3OD) δ 2.54 (s, 3H), 7.70 (t, J=7.8 Hz, 1H), 8.02-8.07 (m, 1H), 8.23-8.28 (m, 1H), 8.45 (t, J=1.9 Hz, 1H) ppm; MS (DCl/NH3) m/z 233 (M+NH4)+.
Reaction SMILES: Br[CH2:2][F:3].[Na].[CH3:5][O:6][C:7](=[O:18])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[CH:9][OH:10].C(OCC)(=O)C>CN(C)C=O>[CH3:5][O:6][C:7](=[O:18])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[CH:9][O:10][CH2:2][F:3]
Reactant: FCBr
Reactant: COC(=O)C(=CO)c1ccccc1C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(=COCF)c1ccccc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 14.9 g of bromofluoromethane in 20 ml of dimethylformamide is added dropwise at 10° C. to a solution of 20 g of the sodium salt of 3-hydroxy-2-(o-tolyl)-acrylic acid methyl ester in 125 ml of dimethylformamide and the reaction mixture is then stirred at room temperature for 2.5 hours. The reaction mixture is then poured onto 400 ml of ice-water and exhaustive extraction is carried out with ethyl acetate. Washing with saturated sodium chloride solution is followed by drying over sodium sulfate, filtering and concentration by evaporation. Chromatography on silica gel with hexane/ethyl acetate (6:1) yields pure 3-fluoromethoxy-2-(o-tolyl)-acrylic acid methyl ester in the form of a colourless oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH:37]=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[C:19]([N:18]([CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:31][CH:30]=2)[CH2:37][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:20]=[CH:21][C:22]=1[F:29]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: O=CC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CC3CCCC3)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (800 mg, 1.93 mmol) in DCE (16 mL) was treated with cyclopentanecarboxaldehyde (Aldrich, 283 mg, 2.89 mmol) then with sodium triacetoxyborohydride (1.22 g, 5.78 mmol). The resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was allowed to cool down, dichloromethane (40 mL) was added and the organic layer was washed twice with water and with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silicagel afforded the title compound as a colorless oil (590 mg, 60%). HPLC, Rt: 6.47 min (purity: 97.1%), LC/MS, M+(ESI): 498.1. 1H NMR (CDCl3) δ: 7.42 (m, 4H), 7.22 (m, 1M), 7.14 (m, 4H), 6.92 (m, 1H), 6.75 (m, 1H), 4.55 (s, 2H), 3.89 (s, 3H), 3.33 (d, 2H), 2.60 (t, J=7.7 Hz, 2H), 2.29 (m, 1H), 1.65 (m, 2H), 1.70-1.46 (m, 6H), 1.42-1.15 (m, 6H), 0.91 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-hydroxy-3-nitrobenzaldehyde (10.0 g, 81.8 mmol), 1-bromooctane (15.8 mmol, 81.8 mmol), and K2CO3 (34.0 g, 0.25 mol) in DMF (150 mL) was heated to reflux for hours. After cooling the reaction back down to room temperature, the reaction mixture was diluted in toluene and the organic layer was washed with 10% HCl, brine, and water. After concentrating in vacuo, the oil was purified by short silica gel plug (10% DCM in n-hexanes). Solvent was dried in vacuo to afford the 4-octyloxy-3-nitrobenzaldehyde as a slightly colored oil.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[F:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1ccccc1F
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccccc1F

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 2-fluoro-benzoic acid to yield (3aR,4S,7aR)-4-(2-fluoro-benzoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=8.923 min; HPLC Method I
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:18][CH2:17][N:16]([C@@:19]4([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]4)[C:10]=3[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:37]>C(Cl)Cl.CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:18][CH2:17][N:16]([C@@:19]4([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]4)[C:10]=3[N:11]=[C:12]([S:14]([CH3:15])=[O:37])[N:13]=2)=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Solvent: ClCCl
Solvent: CS(C)=O
Product: CS(=O)c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a suspension of tert-butyl(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-(methylsulfanyl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (352 mg, 0.794 mmol) in DCM (8 mL) was added m-chloroperoxybenzoic acid (254 mg, 1.03 mmol, 70% purity) in three portions over 1 min at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Four drops of DMSO was added and the reaction mixture was stirred for 5 min. The reaction mixture was purified via HPLC reversed phase column (XBridge C18 30×250 mm, mobile phase: 0%-50% of water with 0.1% EtOAc to acetonitrile with 0.1% EtOAc over 30 min, flow rate 80 mL/min) to give the title compound (200 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 2 H), 7.18 (s, 2 H), 3.89-3.75 (m, 2 H), 3.73-3.62 (m, 3 H), 3.42-3.34 (m, 3 H), 2.82 (s, 3 H), 2.41 (br s, 1 H), 2.15-2.01 (m, 1 H), 1.41 (s, 9 H), 1.33 (s, 3 H). m/z (APCI+) for C21H29N7O3S 460.6 (M+H)+.