Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(C2(C#N)CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3-Methoxyphenyl)acetonitrile (0.52 grams) was added to a solution of sodium hydride (0.212 grams) in DMSO (10 mL) at 0° C. The mixture was warmed to room temperature over 30 minutes. 1,5-Dibromopentane (0.722 mL) was added dropwise as a solution in DMSO (5 mL). This mixture was stirred for 16 hours, then partitioned between ethyl acetate and water. The organic phase was separated and washed with brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The resulting solid was chromatographed on silica gel using ethyl acetate and hexane (3:97) to give the titled compound (0.42 grams).
Reaction SMILES: [Na+].[Cl-].[OH:3]C1C(CC=C(C)C)=C(O)C=CC=1CCCC1C=CC(O)=CC=1.CC(C)=CC[C:30]1[C:31]([OH:49])=[CH:32][CH:33]=[C:34]2[C:39](=[O:40])[CH2:38][C@@H:37]([C:41]3[CH:42]=[CH:43][C:44]([OH:48])=[CH:45][C:46]=3O)[O:36][C:35]=12>CO>[CH2:38]1[C:39](=[O:40])[C:34]2[C:35](=[CH:30][C:31]([OH:49])=[CH:32][C:33]=2[OH:3])[O:36][C@@H:37]1[C:41]1[CH:42]=[CH:43][C:44]([OH:48])=[CH:45][CH:46]=1
Reactant: CC(C)=CCc1c(O)ccc2c1O[C@H](c1ccc(O)cc1O)CC2=O
Reactant: CC(C)=CCc1c(O)ccc(CCCc2ccc(O)cc2)c1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=C1C[C@@H](c2ccc(O)cc2)Oc2cc(O)cc(O)c21

Procedure:
Colorless needles; [α]D20 −7.3° (c 0.15, MeOH); UV (MeOH) λmax (log ε) 288 (3.79), 226 (3.93), 216 (3.92) nm; CD (MeOH) nm Δε271 −5.5; IR (NaCl) γmax 3350, 2927, 1636, 1558 cm−1; 1H NMR (CD3OD, 500 MHz) δ 2.69 (1H, dd, J=2.9 and 17.1 Hz, H-3), 3.10 (1H, dd, J=13.0 and 17.2 Hz, H-3), 5.33 (1H, dd, J=2.9 and 12.9 Hz, H-2), 5.87 (1H, d, J=2.2 Hz, H-6), 5.88 (1H, d, J=2.2, 8.7 Hz, H-8), 6.80 (2H, d, J=8.6 Hz, H-3′), 7.30 (2H, d, J=8.4 Hz, H-2′); 13C NMR (CD3OD, 125 MHz) δ 42.6 (C-3), 79.1 (C-2), 94.8 (C-8), 95.7 (C-6), 101.9 (C-10), 114.9 (C-3′), 127.6 (C-2′), 129.7 (C-1′), 157.6 (C-4′), 163.5 (C-9), 164.1 (C-5), 167.2 (C-7), 196.3 (C-4); EIMS m/z 272 (M+, 88), 239 (6), 190 (15), 179 (24), 153 (100), 120 (50).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:21].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH3:11][O:10][C:4]1[N:3]=[C:2]([OH:21])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Cl)nc(OC)n1
Agent: C1CN2CCN1CC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Product: COc1cc(O)nc(OC)n1
Yield: 34.3 %

Procedure:
A suspension of 4-chloro-2,6-dimethoxy-pyrimidine (4.9 g, 28 mmol), DABCO (6.4 g, 57 mmol) and potassium carbonate (13.8 g, 100 mmol) was refluxed in water (150 ml) for one hour. The mixture was cooled acidified with 5% citric acid and extracted three times with ethyl acetate and three times with DCM with about 105 THF and 10% MeOH. The combined organic phases were dried and evaporated which gave the title compound (1.5 g, 34%), (M+H)+1 157.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[O:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[O:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 72.1 %

Procedure:
3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.200 g, 3.33 mmol) and ethyl formate (0.8 mL, 9.95 mmol) were dissolved in anhydrous ethanol (30 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (6.21 mL, 16.63 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a light yellow precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.931 g, 2.4 mmol, 72%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[S:16][C:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=3F)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[S:16][C:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=3[NH2:30])=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ncc(C(=O)c3cccnc3F)s2)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCN(c2ncc(C(=O)c3cccnc3N)s2)CC1
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
A microwave vial was charged with tert-butyl-4-(5-(2-fluoronicotinoyl)thiazol-2-yl)-1,4-diazepane-1-carboxylate (300 mg, 0.75 mmol) and aqueous ammonium hydroxide (1 ml). The reaction mixture was stirred in the microwave at 110° C. for 25 minutes. The reaction mixture was concentrated in vacuo to afford the title compound (300 mg, 100%). The residue was used in the next step without any further purification. MS (ES+): 405
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>ClCCl>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH:10]1[NH:9][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
200 ml of dichloromethane then 10 ml, i.e. 7.26 g (71.7 mmol) of triethylamine were added to 5 g (29.5 mmol) of 2-aminoindan hydrochloride. The mixture was stirred for 30 min, then 3.4 ml, i.e. 3.84 g (35.4 mmol) of ethyl chloroformate were added dropwise. The mixture was stirred for 30 min, then ice-water and an excess of 1N hydrochloric acid were added. The precipitate was filtered, washed, dried and purified by chromatography on a silica gel column, eluted with an 80:20 mixture of dichloromethane/ethyl acetate. 4.25 g of amorphous solid were isolated.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40](=[O:49])[NH:41][CH2:42][CH:43]1[O:48][CH2:47][CH2:46][NH:45][CH2:44]1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40](=[O:49])[NH:41][CH2:42][CH:43]1[O:48][CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:31])([F:32])[F:30])=[CH:28][C:3]=3[C:2]([F:1])([F:34])[F:33])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NCC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
(4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-morpholin-2-ylmethyl)-carbamic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Morpholin-2-ylmethyl-carbamic acid tert-butyl ester following General Procedure C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[I:18]I>>[I:18][C:15]1[CH:16]=[CH:17][C:9]([CH3:8])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: II
Reactant: Cc1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(I)cc1C(=O)O

Procedure:
Acetic anhydride serving as a dehydrating agent is used in an amount of 0.01 to 2 parts by weight on the basis of 1 part by weight of 2-methylbenzoic acid serving as a starting material, preferably 0.1 to 1.5 parts by weight. Through controlling the amount of acetic anhydride so as to fall within the above ranges, a sufficient reaction-promoting effect can be attained, whereby conversion of 2-methylbenzoic acid serving as a starting material and that of iodine can be enhanced. Thus, 5-iodo-2-methylbenzoic acid can be produced at low cost without increasing load of separation/recovery during the purification step. Notably, in the case in which iodine, iodic acid, periodic acid, or a similar species is dissolved or suspended in water, and the solution or suspension is placed in a reactor, acetic anhydride must be added in an amount in excess of the above amount in order to remove water forming the solution or suspension.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[CH2:21][N:6]1[CH:5]=[C:4]([NH2:1])[CH:8]=[N:7]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cnn(CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a suspension of 4-nitro-1H-pyrazole (500 mg) and potassium carbonate (1.22 g) in DMF (5 mL) was added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.54 g). The reaction mixture was stirred at room temperature for 4 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A suspension of the obtained residue and palladium on carbon (1 g) in methanol (30 mL) was stirred at room temperature for 12 hr under a hydrogen atmosphere, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (490 mg).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][C:31]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(C(F)(F)F)ccc1Cl
Yield: 3.8 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-5-(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 112 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-trifluoromethyl-biphenyl-2-carboxylic acid (5 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 13.19 (br s, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 8.28-8.36 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 7.71-7.82 (m, 4H), 7.52 (d, J=8.1 Hz, 1H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([O:10][C:11]([C:13]1[N:14]=[C:15](O)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH2:7][CH2:8][CH3:9].C(=O)(O)[O-].[Na+].O>C(#N)C>[CH2:6]([O:10][C:11]([C:13]1[N:14]=[C:15]([Br:3])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 4.59 g of phosphorous oxybromide (16 mmol) in 25 ml of anhydrous acetonitrile were added 1.108 g of 1,4-dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (3 mmol) and the mixture was refluxed gently with stirring for 1 h. Then 5.04 g of sodium bicarbonate (60 mmol) were added, followed by the dropwise addition of 8 ml of water. After stirring at ambient temperature for 90 min the mixture was concentrated in vacuo to about one third of its volume, 40 ml of water were added and the mixture was extracted with 30 ml of ethyl acetate. The mixture was filtered by suction. The organic phase was separated, dried over MgSO4, and filtered through a pad of silica gel. Evaporation in vacuo gave 0.885 g of the title compound; 1H NMR (CDCl3): δ=11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40 to 7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>>[O:18]1[C:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[CH:2][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccc(C#N)cc1
Product: N#Cc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 4-Ethynyl-benzonitrile and 2-iodophenol to the title product. Purification by flash chromatography (20% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (337 mg, 77% yield). 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=8.85, 2H), 7.71 (d, J=8.67, 2H), 7.62 (d, J=7.54, 1H), 7.53 (d, J=8.10, 1H), 7.38-7.24 (m, 2H), 7.16 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 155.08, 153.37, 134.25, 132.45, 128.52, 125.45, 124.93, 123.34, 121.40, 118.66, 111.33, 111.28, 104.23. Anal. Calcd. for C15H9NO: C, 82.18; H, 4.14; N, 6.39. Found C, 81.98; H, 4.09; N, 6.15. m.p.: 149° C. (lit., 4145-146° C.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:22]=[C:21]([NH2:23])[N:20]=[CH:19][N:18]=1.O>CO>[C:5]1([C:3]2[N:16]=[C:17]3[CH:22]=[C:21]([NH2:23])[N:20]=[CH:19][N:18]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1cc(N)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
ω-Bromoacetophenone (9.04 g, 45 mmol) and NaHCO3 (4.30 g, 50 mmol) were added to a solution of 4,6-diaminopyrimidine (5.00 g, 0.45 mmol) in methanol (80 ml), and the mixture was heated to reflux (3 h). Upon cooling, water (40 ml) was added, and the suspension was stirred at r.t. (15 min). The precipitated title compound (5.62 g, 59%) was isolated by filtration, washed with small amounts of water and methanol, and dried under vacuum. MS (m/e)=211.1 [M+H+].
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH3:14])[CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1>ClCCl>[Br:1][CH:5]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:4](=[O:3])[CH3:14]
Reactant: CC(=O)Cc1ccc(C#N)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CC(=O)C(Br)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Bromine (5.28 g) in dichloromethane (80 ml) was added dropwise at 25° C. over 1 hour to 4-(2-oxopropyl)benzonitrile in dichloromethane (85 ml). The reaction mixture was stirred for 1/2 hour after the addition was complete. The mixture was washed with brine (50 ml), dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound as a pale red oil (7.55 g, 96%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([OH:31])[C:29]#[CH:30]>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:30]#[C:29][CH2:28][OH:31])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCO
Product: OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol were converted to yield 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as off-white solid, MS: 333(M).
Reaction SMILES: C1(C)C=CC(S([N:10]=[N+:11]=[N-])(=O)=O)=CC=1.[CH3:14][O:15][C:16]([C@@H:19]1[C:22](=[O:23])[NH:21][C@@H:20]1[CH2:24][C:25](=[O:40])[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[N+:10](=[C:26]([C:25](=[O:40])[CH2:24][C@@H:20]1[C@H:19]([C:16]([O:15][CH3:14])([CH3:18])[CH3:17])[C:22](=[O:23])[NH:21]1)[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])=[N-:11]
Reactant: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
A solution of p-toluenesulfonyl azide (470 mg) in acetonitrile (4.23 ml) was added to a solution of 4-nitrobenzyl 4-[(2R,3R)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]-3-oxobutanoate (752 mg) in acetonitrile (15.04 ml) at 0° C. After stirring at 0° C. for 10 minutes, a solution of triethylamine (0.997 ml) in acetonitrile (8.973 ml) was added dropwise thereto. After stirring at 0° C. for an additional 50 minutes, the reaction mixture was evaporated. The residue was chromatographed on silica gel (11 g) eluting with 0-50% ethyl acetate in methylene chloride to give 4-nitrobenzyl 2-diazo-4-[(2R,3R)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]-3-oxobutanoate (733 mg).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C.O>[I:1][C:14]1[CH:13]=[C:12]([O:11][C:10]([F:19])([F:20])[F:9])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(OC(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a suspension of N-iodosuccinimide (6.95 g, 31 mmol) in glacial acetic acid (2 ml) was added 4-trifluoromethoxy phenol (4.0 ml, 31 mmol) and, after 5 minutes, concentrated sulphuric acid (0.5 ml, 9 mmol). The pale brown suspension was stirred at room temperature under nitrogen for 48 hours before diluting with water and extracting with dichloromethane. Organic extract was washed with water, saturated aqueous sodium thiosulphate solution, water, dried over magnesium sulfate and decolourising charcoal added. The resulting suspension was left to stand for 30 minutes before filtering through a short pad of silica gel eluting with dichloromethane. The solvent was evaporated in vacuo to give the title compound as an oil, 8.78 g, 94% yield.
Reaction SMILES: C([O:8][C:9]([C@:11]12[CH2:18][CH2:17][C@@:14]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)=[O:10])C1C=CC=CC=1>C(O)C.O.[Pd]>[CH3:24][O:23][C:21]([CH2:20][CH2:19][C:14]12[CH2:15][CH2:16][C:11]([C:9]([OH:10])=[O:8])([CH2:18][CH2:17]1)[CH2:12][CH2:13]2)=[O:22]
Reactant: COC(=O)C=C[C@]12CC[C@@](C(=O)OCc3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COC(=O)CCC12CCC(C(=O)O)(CC1)CC2

Procedure:
4-(2-Methoxycarbonyl-vinyl)-bicyclo[2.2.2]octane-1-carboxylic acid benzyl ester (XX, Example 95, 35 g, 106.6 mmol) is dissolved in ethyl alcohol/water (9/1, 300 ml) and is placed in a Porter pressure bottle. Palladium on carbon (10%, 5 g) is added and the mixture is hydrogenated (65 psi) for 48 hr. The reaction mixture is filtered through a pad of celite and the combined filtrates were concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 3.58, 2.18, 1.74, 1.44 and 1.38.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:22]3[N:42]=[CH:43][C:44]([C:45]4[CH:46]=[N:47][C:48]5[C:53]([CH:54]=4)=[CH:52][CH:51]=[CH:50][CH:49]=5)=[C:21]3[N:20]=2)[CH2:15][CH2:14]1)=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:24]([Br:1])=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[N:22]3[N:42]=[CH:43][C:44]([C:45]4[CH:46]=[N:47][C:48]5[C:53]([CH:54]=4)=[CH:52][CH:51]=[CH:50][CH:49]=5)=[C:21]3[N:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
N-bromosuccinimide (148 mg, 0.832 mmol) was added to a solution of 4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (500 mg, 0.756 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resulting oil is then purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield the title compound (530 mg, 95% yield) as yellow oil. LC-MS: 740 [M+H].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:33]#[CH:34]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)\[C:5]2[CH:6]=[CH:7][C:2]([C:34]#[C:33][CH2:32][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the above ester (480 mg, 0.908 mmol) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and N-propargylmorpholine (237 mg, 1.89 mmol) was added under argon atmosphere. The solution was cooled, tetrakis(triphenylphosphine)palladium (84 mg, 0.073 mmol) and copper(I) iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture was stirred at ambient temperature for 6 h and then left to stand overnight. The mixture was evaporated in vacuo; the residue was dissolved in dichloromethane (20 mL) and the formed solution was washed with water (2×10 mL). The organic solution was dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 1:1) yielding methyl (Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.