Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].[CH2:3]([S:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>O1CCCC1.Cl>[CH2:3]([S:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCSCCC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSCCCO
Yield: 99.1 %

Procedure:
To a slurry of 147 mg of lithium borohydride in 20 ml of tetrahydrofuran is added slowly with stirring 2.4 g of ethyl 3-(hexadecylthio)propanoate. The mixture is refluxed for 18 hours and poured into water. A few drops of hydrochloric acid is added followed by ether extraction. The organic layer is dried and evaporated to give 2.1 g of the desired product.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH2:6]([NH:13][C:14](=[O:25])[CH2:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH2:15][C:14]([NH:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:25])=[S:4]
Reactant: NNC(N)=S
Reactant: O=C(CCC(=O)c1ccccc1)NCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CCC(=O)NCc1ccccc1)c1ccccc1
Yield: 87.9 %

Procedure:
Thiosemicarbazide (2.30 g, 25.2 mmol) was added to a solution of N-benzyl-4-oxo-4-phenyl-butyramide (4.12 g, 15.4 mmol), prepared in the previous step, in 100 ml of methanol plus 4.2 ml of 1 N HCl plus 4.2 ml of water and the reaction stirred at room temperature for 20 hours. The reaction was cooled in an ice bath and a white solid precipitated. The solid was collected by filtration and dried to give 4.61 g of a white solid. Recrystallization of the solid from ethyl acetate-methanol gave the title compound (2.05 g, 39%) as a white solid, mp 162-164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Yield: 86 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 3.25 (s, 4H), 3.77 (s, 3H), 3.87 (s, 3H), 4.09-4.12 (m, 4H), 6.86-7.00 (m, 3H), 7.12-7.24 (m, 3H), 7.55-7.65 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1ccc(CCBr)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(CCBr)cc1

Procedure:
A solution of [4-(2-bromoethyl)phenyl]acetic acid (48.6 g., 0.2 mole) and sulfuric acid (1.5 ml.) in ethanol (400 ml.) is boiled under reflux for 6 hours. About 300 ml. of the ethanol is removed by distillation at reduced pressure. The residue is diluted with 400 ml. of water. The oily ester is taken up in ether, washed with water and brine, and dried over magnesium sulfate. Evaporation of the ether leaves the title compound as an oil which can be purified by distillation in vacuo.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]([C:32]1[CH:40]=[CH:39][C:35](C(Cl)=O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:41]([N:43]([CH2:47][CH3:48])[CH2:44][CH2:45][NH2:46])[CH3:42]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15](=[O:17])[C:35]2[CH:34]=[CH:33][C:32]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:40][CH:39]=2)[C@H:12]([C:22]([NH:46][CH2:45][CH2:44][N:43]([CH2:47][CH3:48])[CH2:41][CH3:42])=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOCc2ccccc2)CN1C(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 86% purity by LC/MS. MS(ESI+): m/z=529.6.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[CH:15]=[CH:14][C:13](CC(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].CN(C=O)C>ClCCl>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
3.75 ml (7.5 mmoles) of a 2M solution of oxalyl chloride in dichloromethane is added at 20° C. to a solution of 0.9 g (5 mmoles) of 4-nitrophenylacetic acid in a mixture composed of 10 ml of dichloromethane and 0.5 ml of DMF. After agitation for 30 minutes, the solution is concentrated under vacuum. The yellow oil obtained is used without additional purification in the following stage.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[O:16][C:17]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:18]([Br:20])[CH:19]=1>>[Br:20][C:18]1[CH:19]=[C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])[O:16][C:17]=1[Si:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: C[Si](C)(C)c1oc(Br)cc1Br
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Product: C[Si](C)(C)c1oc(N2C[C@@]3(CN4CCC3CC4)OC2=O)cc1Br

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2,4-dibromo-5-(trimethylsilyl)furan. The title compound (577 mg) was obtained as a pale yellow solid, m/z 399, 401 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:9].[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:13]=2[O:12][CH2:11]1.N=C=N.OC1C2N=NNC=2C=CC=1.C(O)C(N)(CO)CO>C(#N)C.ClCCl.CN(C=O)C.C(#N)C>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH:9][C:19]([C:17]1[CH:16]=[CH:15][C:14]2[O:10][CH2:11][O:12][C:13]=2[CH:18]=1)=[O:20]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CC1CCCC(N)C1C
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClCCl
Product: CC1CCCC(NC(=O)c2ccc3c(c2)OCO3)C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3-dimethylcyclohexanamine (20 μmol) and benzo[d][1,3]dioxole-5-carboxylic acid (1.1 eq) were each dissolved in acetonitrile/dichloromethane (200 μL, 2:1). PS-Carbodiimide resin (2 eq) was loaded into a 1.2 mL 96 well Greiner plate, followed by the addition of amine and acid solutions. Hydroxybenzotriazole (1.1 eq) was dissolved in DMF (100 mL) and was added into the reaction well. The reaction was shaken overnight at room temperature. Once the reaction was completed, PS-Trisamine resin (1.5 eq) was added into the reaction mixture and the solution was allowed to shake overnight at room temperature. Acetonitrile (200 mL) was added into the reaction well, and the top clear solution was transferred into a new plate. The solution was evaporated to give N-(2,3-dimethylcyclohexyl)benzo[d][1,3]dioxole-5-carboxamide. MS (M+H, 276.20).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].[I:21]C(F)(F)F>O1CCCC1.CCCCCC>[I:21][C:17]1[S:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: FC(F)(F)I
Reactant: O=C(O)c1cccs1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(I)s1
Temperature: 0 °C

Procedure:
The title compound has been described by Schick, J. W., et al., J. Am. Chem. Soc. 70:286 (1948), and was prepared according to the following procedure. A 25 ml (62.5 mmoles) volume of a 2.5M hexane solution of n-butyllithium was slowly added by syringe to a cooled (dry ice/2-propanol) 100 ml tetrahydrofuran solution of 9.0 ml (64.2 mmoles) of diisopropylamine. The solution was maintained below -60° C. during n-butyllithium addition. After addition, the cooling bath was removed and the solution allowed to reach room temperature (22° C.), and then cooled again below -60° C. To the cooled reaction vessel, 3.2 g (25.0 mmol) of 2-thiophenecarboxylic acid dissolved in 100 ml of tetrahydrofuran was slowly added. Thirty minutes after complete addition of 2-thiophenecarboxylic acid, approximately 17.2 g (87.8 mmoles) of iodotrifluoromethane was condensed into the reaction. After 5 minutes the cooling bath was removed and the reaction warmed to 0° C. and quenched with 50 ml of water. The basic aqueous solution was washed with 500 ml of diethyl ether. The ether solution was extracted with 50 ml of 1N sodium hydroxide and the two aqueous solutions were combined and washed with ether. The basic solution was acidified and extracted three times with 100 ml of diethyl ether. Drying of the organic solution with anhydrous magnesium sulfate followed by filtration and concentration gave a crude solid product. Partial purification was achieved by reprecipitation of the solid product from hot aqueous ethanol to give 3.79 g of slightly impure desired product as a mixture of dark red solid and yellow crystals. Recrystallization of the solid mixture gave 2.18 g (8.58 mmoles, 34% yield) of pure title compound as light yellow needles, m.p. 132°-134° C (hexanes).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24](I)=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28]>CN(C=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:28]#[C:27][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Product: C[Si](C)(C)C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.8 %

Procedure:
To a stirring solution of (S)-2-(5-iodo-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (524 mg, 1.135 mmol), CuI (22 mg, 0.114 mmol) and bis(triphenylphosphine)palladium (II) dichloride (40 mg, 0.056 mmol) in DMF (4 mL) is added TEA (0.47 mL, 3.4 mmol) followed by ethynyl-trimethylsilane (0.17 mL, 1.25 mmol). The reaction mixture is stirred at room temperature overnight and concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (EtOAc/hexanes 5% to 100%) to give a yellow residue which is triturated twice with DCM to afford the title compound (S)-2-(5-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (340 mg, 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-])=O.C(N(CC)CC)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33](Cl)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1.Cl>C1COCC1.CO>[CH:7]([C:6]1[CH:5]=[C:4]([NH:1][C:33]([C:28]2[C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:22][CH:23]=3)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH:11]=[CH:10][CH:9]=1)=[O:8]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1cccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 mL round bottom flask was charged with 3-nitrobenzaldehyde (5.20 g, 34.4 mmol), 100 mL methanol, and Dowex® sulfonic acid resin (e.g., Dowex 50WX4-400, Aldrich catalogue number 21-784-4) in its H+ form (0.57 g), washed with two 5 mL portions of methanol and added as a slurry in 5 mL of methanol. The resulting slurry was heated at reflux for 90 minutes, then stirred overnight at ambient temperature (1H NMR analysis of an aliquot showed a 95:5 ratio of the dimethyl acetal to starting aldehyde). The resin was removed by filtration, and the filtrate concentrated to a pale yellow oil. The acetal was dissolved in 100 mL THF and 10% Pd/C was added (0.52 g). The mixture was placed in a Parr® hydrogenator under 276 kPa (40 psi) hydrogen pressure). After 90 minutes, and three recharges of hydrogen, the pressure of hydrogen held steady and the reaction vessel mixture was purged with nitrogen. The catalyst was removed by filtration through Celite®, and rinsed with four 50 mL portions of THF. The filtrate was treated with triethylamine (10.6 mL, 76 mmol) followed by 4'-trifluoromethyl-biphenyl-2-carboxylic acid chloride (9.8 g, 34 mmol) added, as a solution in 10 mL THF, dropwise over 15 minutes. The resulting slurry was stirred for 20 hours at ambient temperature. 1 N HCl (aqueous) (100 mL) was then added and the mixture was stirred vigorously for 2 hours. The bulk of the THF was then removed on a rotary evaporator. The aqueous layer was extracted with three 50 mL portions of isopropyl ether/ethyl acetate (3:1 v/v). The combined organic extracts were washed twice with 1 N HCl [aq], two times with saturated aqueous NaHCO3 and once with brine, and then dried over MgSO4, filtered, and concentrated to give a white solid. Recrystallization from 4:1 hexanes ethyl acetate (250 mL) provided the title product as a powdery, white solid (10.5 g, 83% yield). 1H NMR: (CDCl3): δ 9.92 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.69-7.67 (m, 3H), 7.62-7.52 (m, 5H), 7.46-7.42 (m, 3H), 7.06 (br s, 1H). MS (electron impact): 369 (M+, 20), 249 (100).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: II
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(I)nc1Br
Reaction time: 1 h

Procedure:
To a solution of 2-bromopyridin-3-ol (1.00 g, 5.80 mmol) in water (30 mL) was added Na2CO3 (1.23 g, 11.60 mmol) and I2 (1.53 g, 5.80 mmol). After 1 hour, the reaction was quenched with 1 N HCl (20 mL), extracted with EtOAc (2×100 mL), and washed with aq. NaHSO3 and brine (50 mL each). The organic layer was dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (20 to 40% EtOAc/hexanes) afforded 2-bromo-6-iodopyridin-3-ol. Rf=0.44 (25% EtOAc/hexanes). LCMS=301.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.56 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 5.65 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17].CCO.C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])=[CH:15][C:16]([NH2:17])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(N)cc2C(C)(C)C)cc1

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h, cooled to room temp., and poured into a mixture of EtO (100 mL) and a 10% Na2CO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The solid residue was washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25 g): 1H-NMR (DMSO-d6) δ 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H).
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.C(S(O)(=O)=O)CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=C=O>C(Cl)(Cl)Cl>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:1][S:2][CH3:4])[C:16]=1[NH2:21]
Reactant: CS(C)=O
Reactant: COc1ccccc1N=C=O
Agent: CCCCS(=O)(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cccc(CSC)c1N
Product: COc1ccccc1N
Temperature: 25 °C
Yield: 67.6 %
Yield: 22.4 %

Procedure:
To a solution of 1.429 g (0.018 moles) of dry dimethyl sulfoxide and 2.27 g (0.015 moles) of dry n-butanesulfonic acid in 13 ml of dry chloroform, was added 2.2110 g (0.0148 moles) of o-methoxyphenyl isocyanate. After thirty minutes at room temperature, the reaction mixture was refluxed for three and a half hours. After cooling to room temperature, the reaction mixture was poured into 180 ml of ice-cold 10% aqueous sodium hydroxide solution. After extracting with methylene chloride, the organic layer was dried over anhydrous sodium carbonate, filtered and 0.10 g of succinimide was added. The resulting solution was concentrated to 100 ml and then refluxed for twenty hours. This solution was cooled, extracted with 10% aqueous sodium hydroxide solution and the organic layer dried over anhydrous magnesium sulfate and filtered. At this point, tridecane was added as an internal standard and the solution was analyzed by gas chromatography. In this manner, there was obtained 0.338 g (22.4%) of o-methoxyaniline and 1.8319 g (67.6%) of 2 -methoxy-6-(methylthiomethyl)aniline. The results are included in Table II.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:35]([O-])(=[O:37])[CH3:36].[Na+]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:35]([O:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@@:2]1([F:1])[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH:5]=[CH:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)[O-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Reaction time: 40 h
Yield: 70.7 %

Procedure:
A solution of 9-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (2.0 g) in a mixture of acetic anhydride (20 ml) and acetic acid (10 ml) containing p-toluenesulfonic acid (200 mg) is kept at room temperature for 40 hours. Sodium acetate (1.0 g) is added and the mixture is evaporated in vacuo. The residue is diluted with water and extracted with chloroform. The chloroform extracts are combined, washed with a dilute sodium bicarbonate solution and water, dried, evaporated and the residue is chromatographed on a column of silica gel to afford the title compound (1.6 g), melting point 229°-230° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:24][CH2:25][CH3:26])[C:13](I)=[C:14]([O:16][S:17]([CH:20]3[CH2:22][CH2:21]3)(=[O:19])=[O:18])[CH:15]=2)=[CH:4][N:3]=1.I[C:28]1[CH:29]=[C:30]([F:41])[CH:31]=[C:32]([NH:34]C(=O)C(F)(F)F)[CH:33]=1.C(O)C>O1CCOCC1.C(COC)OC>[NH2:34][C:32]1[CH:33]=[C:28]([C:13]2[C:12]([O:24][CH2:25][CH3:26])=[CH:11][C:10]([CH2:9][C:5]3[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:15][C:14]=2[O:16][S:17]([CH:20]2[CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:29]=[C:30]([F:41])[CH:31]=1
Reactant: O=C(Nc1cc(F)cc(I)c1)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CC2)c1I
Solvent: C1COCCO1
Solvent: CCO
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CC2)c1-c1cc(N)cc(F)c1
Yield: 30 %

Procedure:
Starting from cyclopropanesulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester (294 mg; 0.60 mmol) and N-(5-iodo-3-fluoro-phenyl)-2,2,2-trifluoroacetamide (preparation described in example 4t) (333 mg; 1.0 mmol) (first step in 12 ml dioxane instead of dimethylformarmide with bis-triphenylphosphine-palladium dichloride (56 mg; 0.08 mmol) and second step in dimethoxyethane (8 ml) and ethanol (2 ml) with tetrakis-triphenylphosphine-palladium (69 mg; 0.06 mmol)), 147 mg (30%) cyclopropanesulphonic acid 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-5′-fluoro-biphenyl-2-yl ester are obtained as a colourless powder.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.[OH-].[Na+]>ClCCl>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:3])[CH3:6]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccccc1-c1ccccc1

Procedure:
A solution of 21.7 g (0.2 mol) of ethyl chloroformate in 20 ml of dichloromethane is slowly added dropwise to a mixture of 25 g of 2-aminobiphenyl (0.148 mol) and 79 g of pyridine (1 mol) in 150 ml of dichloromethane while stirring. After stirring for 12 hours, 100 ml of 10% strength NaOH are added. The aqueous phase is separated off and shaken with dichloromethane. After the dichloromethane extract has been dried over sodium sulfate, the solvent is removed under reduced pressure and the red oil which remains is worked up by column chromatography (silica gel 60, 0.043 . . . 0.060 mm, eluant: hexane/ethyl acetate=9:1). Yield: 31.7 g=89%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.[C:45]1([CH:51]([C@H:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[OH:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:54]2[CH2:55][CH2:56][CH2:57][C@@H:53]2[CH:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[OH:52])=[O:14])=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)[C@H]1CCCN1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC[C@@H]2C(O)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (22 mg, 0.11 mmol) in acetonitrile (5 mL) was added o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (45 mg, 0.14 mmol, 1.3 eq.), pyridine (34 μL, 0.42 mmol, 4 eq.), and phenyl[(2R)-pyrrolidin-2-yl]methanol hydrochloride (25 mg, 0.12 mmol, 1.1 eq.). The reaction mixture was stirred at ambient temperature for 20 h and at 40° C. for an additional 2 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to yield the product as a white solid. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1625.