Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClOC(C)(C)C.[CH3:7][N:8]1[C@H:22]2[C@@H:12]([C:13]3[CH:14]=[C:15]([N+:24]([O-:26])=[O:25])[CH:16]=[C:17]4[C:23]=3[CH:20]([CH2:21]2)[CH2:19][NH:18]4)[CH2:11][C@@H:10]([NH:27][C:28](=[O:34])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:9]1.CSC.C(N(CC)CC)C.CC[O-].[Na+]>C(Cl)Cl.C(O)C.O>[CH3:7][N:8]1[C@H:22]2[C@@H:12]([C:13]3[CH:14]=[C:15]([N+:24]([O-:26])=[O:25])[CH:16]=[C:17]4[C:23]=3[C:20]([CH2:21]2)=[CH:19][NH:18]4)[CH2:11][C@@H:10]([NH:27][C:28](=[O:34])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:9]1
Reactant: CCN(CC)C(=O)N[C@@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3C(CN4)C[C@H]2N(C)C1
Agent: CC(C)(C)OCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CSC
Solvent: O
Product: CCN(CC)C(=O)N[C@@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
A solution of 0.4 mmol of tert-butyl hypochlorite in 2 ml of methylene chloride is added dropwise to a solution of 0.3 mmol of 3-(2,3-dihydro-6-methyl-13-nitro-8β-ergolinyl)-1,1-diethylurea, 0.4 mmol of dimethyl sulfide, and 0.3 mmol of triethylamine in 5 ml of methylene choride at -70° C., and the mixture is agitated for 2 hours. Then a solution of 2 mmol of sodium ethylate in 2 ml of ethanol is added thereto within 10 minutes, and the mixture is warmed up to room temperature within 2 hours, whereafter it is combined with water, extracted with methylene chloride, the organic phase is dried and evaporated. Chromatography on silica gel with methylene chloride/methanol (5%) yields 30 mg of 3-(6-methyl-13-nitro-8β-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH2:14])=[CH:12][NH:11][N:10]=1.[N:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:18]2=[C:17]([C:24](O)=[O:25])[CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH:14][C:24]([C:17]2[CH:16]=[N:15][N:19]3[CH:20]=[CH:21][CH:22]=[N:23][C:18]=23)=[O:25])=[CH:12][NH:11][N:10]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: Cc1ccc(C)c(-c2n[nH]cc2N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3cccnc23)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A mixture of 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine (0.300 g, 1.60 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (289.2 mg, 1.773 mmol, 1.11 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (1.087 g, 2.096 mmol, 1.31 eq), N,N-diisopropylethylamine (1.0 mL, 5.7 mmol, 3.6 eq), and 4-dimethylaminopyridine (42.3 mg, 0.346 mmol, 0.22 eq) in 8.0 mL N,N-dimethylformamide was stirred at 50° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (40 to 100% ethyl acetate in dichloromethane) to yield 299.8 mg (56%) of N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=333.3; 1H NMR (400 MHz, DMSO-d6) δ: 9.67 (s, 0.7H), 9.55 (s, 0.3H), 9.32 (d, 1H), 8.64 (s, 1H), 8.49 (d, 1H), 8.27 (s, 1H), 7.29 (d, 1H), 7.22 (m, 3H), 2.34 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:19][O:20][C:21]([F:31])([F:30])[C:22]([F:29])([F:28])[CH2:23][C:24]([F:27])([F:26])[F:25])([CH2:6][O:7][C:8]([F:18])([F:17])[C:9]([F:16])([F:15])[CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:4][OH:5].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl.CS(Cl)(=O)=O>[S:33]([O:5][CH2:4][C:3]([CH2:6][O:7][C:8]([F:17])([F:18])[C:9]([F:15])([F:16])[CH2:10][C:11]([F:14])([F:13])[F:12])([CH2:19][O:20][C:21]([F:30])([F:31])[C:22]([F:28])([F:29])[CH2:23][C:24]([F:25])([F:26])[F:27])[CH2:2][Br:1])(=[O:35])(=[O:34])[CH3:32]
Reactant: OCC(CBr)(COC(F)(F)C(F)(F)CC(F)(F)F)COC(F)(F)C(F)(F)CC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(CBr)(COC(F)(F)C(F)(F)CC(F)(F)F)COC(F)(F)C(F)(F)CC(F)(F)F
Yield: 95.1 %

Procedure:
In a manner similar to that described above, 3-bromo-2,2-bis-(heptafluorobutoxymethyl)-1-propanol (250.0 g, 0.44 mole) was reacted with methanesulfonyl chloride (58.45 g, 0.51 mole) and triethylamine (52.62 g, 0.52 mole) in methylene chloride (400+200 ml). Additional methanesulfonyl chloride (2.96 g, 0.03 mole) was added to bring the reaction to completion. Washing and removal of the solvent gave 268.4 g (95.2%) of 3-bromo-2,2-bis(heptafluorobutoxymethyl)-1-propanol mesylate (4), a yellow oil: IR 2940, 1350, 1223, 1176, and 1120 cm-1 ; 1H NMR (CDCl3) 3.02 (s, 3H), 3.49 (s, 2H), 3.68 (s, 4H), 3.97 (t, J=13.3 Hz, 4H), and 4.24 (s, 2H); 13C NMR (CDCl3) 31.66, 36.64, 44.60, 67.81 (t, J=26.44), 68.36, and 70.30. Anal. Calcd for C14H15BrF14O5S: C, 26.22; H, 2.36; Br, 12.46, F, 41.48. Found: C, 25.95; H, 2.33; Br, 12.88.
Reaction SMILES: Cl.N[OH:3].[C:4]1([C:10]2[O:14][C:13]([CH:15]=[N:16]N3CC(=O)NC3=O)=[N:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C>C(O)(=O)C>[C:4]1([C:10]2[O:14][C:13]([CH:15]=[N:16][OH:3])=[N:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CN(N=Cc2ncc(-c3ccccc3)o2)C(=O)N1
Reactant: NO
Agent: C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: ON=Cc1ncc(-c2ccccc2)o1

Procedure:
Hydroxylamine hydrochloride (54 g, 0.78 mole) and 1-[[[5-phenyl-2-oxazolyl]methylene]amino]-2,4-imidazolidinedione (105 g, 0.39 mole) were refluxed with stirring in a solution of water (100 ml) and glacial acetic acid (1.0 l.) for five hrs. An additional 54 g of hydroxylamine hydrochloride was added while the mixture was refluxed another five hrs. The hot solution was treated with Darco, filtered and poured into water (5.0 l.). The solid was again refluxed in a mixture of hydroxylamine hydrochloride (50 g), acetic anhydride (800 ml) and water (80 ml) for four hrs. The solution was cooled, poured into water (3.0 l.) and the resulting solid was collected and dried (48 g, 65%). Recrystallization of a sample from acetonitrile gave product of analytical purity, m.p. 208°-210°.
Reaction SMILES: O[C@@H:2]1[CH2:22][C:21]2[C@:16]([CH3:24])([CH:17]=[CH:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@@H:3]1[C@H:4]1[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@H:7]([CH:8]([CH:10]=O)[CH3:9])[CH2:6][CH2:5]1.[CH3:26][C:27]([CH3:32])([CH2:30][OH:31])[CH2:28][OH:29].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:27]1([CH3:32])[CH2:30][O:31][CH:10]([CH:8]([C@@H:7]2[C@:12]3([CH3:25])[C@H:4]([C@H:3]4[C@H:15]([CH2:14][CH2:13]3)[C@:16]3([CH3:24])[C:21](=[CH:20][C:19](=[O:23])[CH:18]=[CH:17]3)[CH:22]=[CH:2]4)[CH2:5][CH2:6]2)[CH3:9])[O:29][CH2:28]1
Reactant: CC(C)(CO)CO
Reactant: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 30.7 %

Procedure:
In 200 ml of benzene were dissolved 5.00 g (14.6 moles) of 7α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde and 4.56 g (43.8 mmoles) of 2,2-dimethyl-1,3-propanediol, followed by addition of 100 mg of p-toluenesulfonic acid. The mixture was refluxed for 5 hours, with the byproduct water being constantly removed from the reaction system by means of a Dean-Stark trap. The reaction mixture was cooled to room temperature and washed with aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ether-hexane (70:30, v/v) and the extract was combined with the organic layer. This mixture was washed with aqueous sodium chloride solution and dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eleuent: ethyl acetate-hexane=1:10, v/v) to recover 5.53 g of 20-(5,5-dimethyl-1,3 -dioxan-2-yl)pregna-1,4,6-trien-3-one (yield: 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[NH:19]1[CH2:23][C@H:22]([OH:24])[C@@H:21]([OH:25])[CH2:20]1>>[OH:25][C@@H:21]1[C@@H:22]([OH:24])[CH2:23][N:19]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:20]1
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(C(=O)N3C[C@H](O)[C@@H](O)C3)cc2)OC1(C)C

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (3S,4S)-pyrrolidine-3,4-diol.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([OH:45])[C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1.O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:45])[C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc(O)cc1
Temperature: 90 °C
Yield: 58.9 %

Procedure:
N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of synephrine (0.137 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature, poured into water (25 mL), and extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (CH2Cl2/methanol; 98/2, 97/3) followed by recrystallization from ethyl acetate/methanol to yield 0.120 g of the title compound as a white solid. Physical characteristics. M.p. 117-122° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 9.21, 8.54, 7.41-7.33, 7.09, 6.85, 6.65, 4.88, 4.614.57, 4.55, 3.89, 3.71, 2.58-2.45, 2.30; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.8, 156.1, 153.2, 150.9, 141.2, 137.1, 132.9, 132.8, 128.9, 128.7, 127.4, 116.6, 115.3, 114.8, 106.6, 69.5, 64.0, 54.0, 42.6, 42.2, 37.8; MS (ESI+) m/z 496 (M+H)+
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([C:23]([F:26])([F:25])[F:24])([C:19]([F:22])([F:21])[F:20])[OH:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>[Pd]>[F:26][C:23]([F:24])([F:25])[C:17]([C:19]([F:22])([F:20])[F:21])([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2)[OH:18]
Reactant: OC(c1ccc2c(c1)CCN2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: Cl
Product: OC(c1ccc2c(c1)CCN2)(C(F)(F)F)C(F)(F)F
Yield: 77.8 %

Procedure:
A mixture of 55 g (0.15 mole) of 1-benzyl-α,α-bis(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol, 200 ml of alcohol, 32 ml of concentrated hydrochloric acid, and 2 g of 10% palladium on charcoal is shaken in a Parr apparatus at an initial pressure of three atmospheres until no further change of pressure is observed. The catalyst is filtered off, and the filtrate is evaporated. The residue is distributed between ether and 8 N ammonium hydroxide. The ether layer is separated, washed (saturated sodium chloride solution), dried (magnesium sulfate), and evaporated. Dibutyl ether is added to the residue, and the solution is cooled in an ice bath. The crystals are filtered off to give 33.3 g (80%) of α,α-bis(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol, m.p. 161°-162°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH2:39][CH2:38]1.N1CCCC1.C(Cl)Cl>C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:47][C:43]([N:40]4[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]4)([CH3:44])[CH3:46])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CC(C)(C=O)N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
A mixture of (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (150 mg, 0.31 mmol), 2-(4-hydroxy-1-piperidyl)-2-methyl-propanal (167 mg, 0.98 mmol), pyrrolidine (0.03 mL, 0.31 mmol) and DCM (10 mL) was stirred at room temp for 2 days and then diluted with aq. NaHCO3 (40 mL) and extracted with DCM. The organic was dried (MgSO4), filtered and concentrated to an oil. The crude material was purified at Isolera (25 g column: 30% iPrOH/DCM) to obtain the product which was isolated by lyophilization to provide 61 mg (32% yield) of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-hydroxypiperidin-1-yl)-4-methylpent-2-enenitrile as a powder. MS (pos. ion) m/z: 625 (M+1).
Reaction SMILES: [Si](C[Li])(C)(C)C.I[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=1>CCCCCCC.C1COCC1.[Zn+2].[Br-].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:19]1[N:18]=[C:17]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cnc(I)c(C)c1
Reactant: Clc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1cnc(-c2cccc(Cl)n2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
An oven-dried flask under N2 was charged with TMS-CH2Li (2.57 mmol, 1M in pentane) and cooled to 0° C. Then a solution of the 2-iodo-3,5-dimethylpyridine (300 mg, 1.29 mmol) in heptane (4.3 mL) was added dropwise, and the resulting mixture was stirred at 0° C. for 1 h. The solution was cooled to −78° C., and 2 mL THF was added. A solution of ZnBr2 (435 mg, 1.53 mmol) in THF (4.3 mL, cooled to 0° C.) was added dropwise. The resulting mixture was stirred vigorously at −78° C. for 30 min, then warmed to 0° C. for 1 h. Solid 2-bromo-6-chloropyridine (371 mg, 1.93 mmol) and Pd(PPh3)4 (74 mg, 5 mol %) were added. The reaction flask was evacuated and back-filled with N2 (3×) then heated to 65° C. After 20 h, the reaction was removed from heat and quenched with saturated aqueous ammonium chloride. The biphasic mixture was transferred to a separation funnel and extracted with EtOAc (3×). The combined organics were washed with 1M Na2S2O3, saturated aqueous sodium bicarbonate, water, and brine, then dried over MgSO4, filtered, and concentrated to get crude product. Purified on Biotage 40S column, eluting with 0-20% EtOAc/heptane to afford 166 mg (59%) of the title compound as an orange oil. LCMS and NMR showed desired product >95% pure. m/z (APCI+) for C12H11N2Cl=219.00 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (s, 1 H) 7.95-8.01 (m, 1 H) 7.88-7.94 (m, 1 H) 7.58 (s, 1 H) 7.53 (d, J=7.83 Hz, 1 H) 2.47 (s, 3 H) 2.33 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]([Cl:11])[CH:7]=2)[C:15](=[O:14])[CH:16]=1
Reactant: NNCc1cc(Cl)ccc1F
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)ccc2F)[nH]1
Reaction time: 2 h

Procedure:
21.6 g of 2-fluoro-5-chlorobenzylhydrazine were added dropwise under nitrogen to a solution of 19.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 0.5 g of p-toluenesulphonic acid in 100 ml of ethanol, in the course of which the temperature rose from 20° to 30°. After stirring for 2 hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 160°, 17 g (57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: Fc1ccc(CS)cc1
Agent: [Na]
Product: Fc1ccc(C(/C=C\c2ccc(Cl)cc2)SC(/C=C\c2ccc(Cl)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 82% yield following oxidation. 1HNMR (CDC13) δ4.60 (2H, s), 6.70 (1H, d, JH,H=11.78), 7.18-7.60 (8H aromatic+1H ethylenic).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Nc2cc(Cl)nc(SC)n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,6-dichloro-2-(methylthio)pyrimidine (1 g), ethyl 6-aminonicotinate (0.85 g) and NaHMDS (10.3 mL, 1M in THF) in THF (50 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×150 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4 and concentrated to give ethyl 6-(6-chloro-2-(methylthio)pyrimidin-4-ylamino)nicotinate which was used as was.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[OH:9])[CH:6]=1.[F:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29](O)=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[O:9][C:29]2[CH:30]=[CH:31][C:22]([CH2:21][CH2:20][C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:34][CH:33]=3)=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:6]=1
Reactant: Cc1cn(CC(O)c2nccs2)cn1
Reactant: COC(=O)c1cc(O)ccc1CCc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(Cn2cnc(C)c2)c2nccs2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
A stirred mixture of 2-(4-methylimidazol-1-yl)-1-(thiazol-2-yl)ethanol (1.35 g, 6.46 mM), methyl 2-(4-fluorophenethyl)-5-hydroxybenzoate (1.95 g, 7.1 mM) and triphenylphosphine (1.86 g, 7.1 mM) in dry THF was cooled in an ice bath, and treated with DEAD (1.24 g, 7.1 mM). The mixture was allowed to warm to ambient temperature, stirred for 18 hours and evaporated to dryness. The product was purified on silica using methanol/dichloromethane (3→10%) as eluant to give methyl 5-[2-(4-methylimidazol-1-yl)-1-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoate (1.45 g, 48%).
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[C:20]2[S:24][C:23]([CH3:25])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(C(OCC)=O)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>C1C=CC=CC=1>[CH3:25][C:23]1[S:24][C:20]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:14][CH:15]=2)=[O:26])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(C(=O)c2ccc(C)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)c2ccc(C(C)C(=O)O)cc2)s1
Reaction time: 0.17 h

Procedure:
A mixture of 15.5 parts of diethyl 2-methyl-2-[p-(5-methyl-2-thenoyl)phenyl]malonate and 120 parts of sodium hydroxide solution 5% is stirred and refluxed for 5 hours. The reaction mixture is cooled and shaken twice with 80 parts of benzene. The aqueous phase is acidified with concentrated hydrochloric acid solution. After standing for 10 minutes, the product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The residue is triturated in petroleumether. The crude product is filtered off and purified by column-chromatography using a mixture of chloroform and 10% of methanol. The pure fractions are collected and the solvent is evaporated. The residue is crystallized from acetonitrile at -20°0 C, yielding p-(5-methyl-2-thenoyl)hydratropic acid; mp. 93.7° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[C:7]=1[CH3:25])C.C(OC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)C.[H-].[Na+].BrC(C1C=CC=CC=1)C>>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18])[C:7]([CH3:25])=[C:6]2[CH2:5][C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)Cc1c(C)n(C(C)c2ccccc2)c2ccc(OC)cc12
Agent: CC(Br)c1ccccc1
Agent: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: [H-]
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(C)c1ccccc1
Yield: 22 %

Procedure:
5-Methoxy-2-methyl-1-(1-phenylethyl)-1H-indole-3-acetic acid ethyl ester. Using the procedure described in Example 1, Part F, 494 mg (2 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester was reacted with 80 mg (2 mmol) of 60% NaH/mineral oil and 0.27 mL (2 mmol) of (1-bromoethyl)benzene and after chromatography on silica (eluting with 25% EtOAc/hexane) there was obtained 160 mg (22%) of 5-methoxy-2-methyl-1-(1-phenylethyl)1H-indole-3-acetic acid acid ethyl ester as an oil.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[N-]=C=O.[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12>>[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:6]([NH2:5])=[O:7])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Agent: [N-]=C=O
Product: NC(=O)Nc1cccc(N2CN=c3occc3=C2N)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using chlorosulfonyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 270 [M+H]+.