Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:3][CH2:2]1.[I:15]I.S(=O)(=O)(O)O.O>CC(O)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[C:13]([I:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: II
Reactant: COC(=O)c1ccc(C2CC2)cc1C
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(C2CC2)cc1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 142.1, 2.68 g, 13.4 mmol, 1.00 equiv, 95%) in AcOH (50 mL) were added NaIO4 (1.51 g, 7.08 mmol, 0.50 equiv), I2 (3.58 g, 14.1 mmol, 1.00 equiv), and sulfuric acid (201 mg, 2.01 mmol, 0.15 equiv, 98%). The reaction mixture was stirred at 110° C. overnight. After cooling to ambient temperature, 100 mL of water was added. The resulting mixture was diluted with 100 mL of ethyl acetate, then washed with 3×30 mL of Na2S2O3 (aq., sat.) and 1×30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via silica gel column chromatography with ethyl acetate/petroleum ether (1/50) as eluent to yield 2.00 g (45%) of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#N)=[CH:12][CH:11]=2)=[C:4]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:3]=1.[OH-:25].[K+].C[OH:28]>>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:28])=[O:25])=[CH:12][CH:11]=2)=[C:4]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:3]=1
Reactant: [OH-]
Reactant: CO
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Agent: [K+]
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1

Procedure:
A mixture of the product from step (vii) (1.2 g) and KOH (5M in water, 5 ml) in MeOH (15 ml) was heated under reflux for 18 h. The solvent was evaporated under reduced pressure and the residue dissolved in water (15 ml). The solution was adjusted to pH7 with 2M HCl then the solid filtered, washed with water then ether to afford the subtitle compound, 1.13 g LC-MS m/z 343 multimode+
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:5]([CH2:7][C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[K+]>O>[CH3:1][C:2]1[O:3][C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)Cc1nc(C)oc1-c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(CC(=O)O)c(-c2ccco2)o1
Yield: 56.8 %

Procedure:
1.1 g of ethyl 2-[2-methyl-5-(2-furyl)-4-oxazolyl]acetate, 20 ml of methanol, 5 ml of water and 0.7 g of potassium hydroxide are treated in the same manner as described in Example 16. 0.55 g of 2-[2-methyl-5-(2-furyl)-4-oxazolyl]acetic acid is obtained. Yield: 56.5%
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>O>[C:27]1(=[O:36])[N:1]([CH:2]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N#Cc1ccc(C(N)CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a stirred mixture of 3-amino-3-(4-cyanophenyl)propionic acid (3.80 g, 20.0 mmol) and sodium carbonate (2.23 g, 21 mmol) in 100 mL of water is added N-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 2 hour, the reaction slurry is filtered and the pH of the stirred filtrate adjusted to 1-2 with 4 N hydrochloric acid. The resulting gel is extracted with ethyl acetate (3×30 mL). The extract is dried over magnesium sulfate and concentrated in vacuo. The crude product is recrystallized from 10% aqueous acetonitrile and then recrystallized from 20% aqueous methanol. The product is dried in vacuo (60° C., <1 mm) to afford 1.5 g (23%) of 3-phthalimido-3-(4-cyanophenyl)propionic acid as a white powder: mp 134°-137° C.; 1H NMR (dmso-d6, 250 MHz) δ 12.5 (br s, 1H), 7.95-7.56 (m, 8 H),. 5.76 (t, 1 H, J=7.7), 3.57-3.15 (m, 2 H); 13C NMR (dmso-d6) δ 171.5, 167.6, 144.2, 134.8, 132.6, 131.1, 128.1, 123.3, 118.5, 49.7, 35.5.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[B:15]([OH:17])[OH:16].BrC1C=CC2C=CC3C(C=2C=1)=CC=CC=3>>[CH:4]1[C:5]2[CH:14]=[CH:13][C:12]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:6]=2[CH:1]=[C:2]([B:15]([OH:16])[OH:17])[CH:3]=1
Reactant: OB(O)c1ccc2c(ccc3ccccc32)c1
Agent: Brc1ccc2ccc3ccccc3c2c1
Product: OB(O)c1ccc2ccc3ccccc3c2c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of phenanthrene-2-boronic acid except that commercially available 3-bromophenanthrene was used instead of 2-iodophenanthrene.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30]>C(OCC)(=O)C.CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CC(NC(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.45 g, 10 mmol) in ethyl acetate (20 mL) and methanol (5 mL) was added DIPEA (0.15 g, 1.14 mmol) followed by ethyl trifluoroacetate (1.54 g, 11 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid which was used directly to the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C([N:25](C(C)C)CC)(C)C>C(Cl)Cl>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O-:10])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH3+:25])[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCc1cccnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: [NH3+]CCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 3-(3-pyridyl)propanol (3.5 mL, 27.12 mmoles) in methylene chloride (15 mL) at 0° C. was treated with p-toluenesulfonyl chloride (6.7219 g, 1.3 equiv.) and diisopropylethylamine (6.14 mL, 1.3 equiv.). After 10 minutes, the mixture was warmed to room temperature. After a further 4 hours, the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and evaporated. the residue was chromatographed on silica, eluting with ethyl acetate, to give a thick, pale-yellow oil which was immediately dissolved in saturated ammonialmethanol (165 mL). This was left to stand at room temperature for 5 days at which time the solvent was removed under reduced pressure. The residue was dried under high vacuum and then dissolved as far as possible in ether (150 mL). The resulting solid product was collected by filtration, washed with ether, and dried in vacuo (6.3051 g, 76%).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([C:20]2([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([C:20]3([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:17][N:16]=2)[CH:15]=1
Reactant: CN(C)C1(C(=O)NNc2ccc(F)cn2)CCCC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C1(c2nnc3ccc(F)cn23)CCCC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 78.6 %

Procedure:
Hexachloroethane (503 mg, 2.12 mmol) was added portionwise over 5 minutes at RT to a stirred mixture of Intermediate 99b (282 mg, 1.06 mmol), triethylamine (590 μL, 4.24 mmol) and triphenylphosphine (555 mg, 2.12 mmol) in THF (11 mL). The reaction mixture was stirred at 50° C. for 2.5 h and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 2M NH3 in MeOH to give the title compound (207 mg, 79%). 1H NMR (400 MHz, CDCl3): 1.67-1.78 (4H, m), 2.10-2.22 (8H, m), 2.24-2.34 (2H, m), 7.15 (1H, ddd, J=10.0, 7.4, 2.3 Hz), 7.69 (1H, dd, J=10.0, 5.0 Hz), 8.65-8.68 (1H, m).
Reaction SMILES: [C:1](Cl)(=O)C.C(N(CC)CC)C.CO.[C:14]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([N+:27]([O-:29])=[O:28])([CH2:20]3)[CH2:18]1)[CH2:24]2)([OH:16])=[O:15]>CN(C=O)C>[CH3:1][O:15][C:14]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([N+:27]([O-:29])=[O:28])([CH2:20]3)[CH2:18]1)[CH2:24]2)=[O:16]
Reactant: CC(=O)Cl
Reactant: O=C(O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-nitroadamantane obtained by the method of Example 42 was dissolved in 10ml of DMF. To the mixture, 15 mmole of acetyl chloride was added dropwise over 30 minutes. The mixture was heated to begin to reflux around the conclusion of the addition. After refluxing for 2 hours, the mixture was cooled, 20 mmole of triethylamine was added, and then 11 mmole of methanol was added dropwise over 30 minutes while retaining the temperature of the mixture at 10° C. or less followed by stirring for more 2 hours. As a result, the conversion of 1-carboxy-3-nitroadamantane was 99%, and 1-methoxycarbonyl-3-nitroadamantane (yield 95%) was formed.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:27]1([CH:33](O)[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.O>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:11])[CH2:3]2
Reactant: OC(Cc1ccccc1)c1ccccc1
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(OC(Cc1ccccc1)c1ccccc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (160 mg, 0.83 mmol), EDC (290 mg, 1.51 mmol), and HOBT (232 mg, 1.51 mmol) were dissolved in dry DMF (8 ml). 1,2-Diphenylethanol (150 mg, 0.76 mmol) and TEA (0.32 ml, 2.27 mmol) were added, and the resulting mixture was stirred at room temperature overnight. Then quinuclidine-3-carboxylic acid hydrochloride (72.5 mg, 0.38 mmol), EDC (87 mg, 0.45 mmol), and HOBT (57.9 mg, 0.38 mmol) were added followed by TEA (0.16 ml, 1.13 mmol), and the mixture was stirred for additional 32 hours. The mixture was diluted with water and extracted three times with Et2O. The organic phases were collected, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude residue was purified by flash chromatography (DCM/MeOH=9/1) to obtain 1,2-diphenylethyl quinuclidine-3-carboxylate (136 mg, racemic mixture).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.Cl[C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].C(N(CC)CC)C.[NH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43]>C(Cl)Cl.[Au]>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][O:16][C:18](=[O:19])[NH:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: NCCOCCO
Agent: [Au]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCOCCO)OCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring slurry of 9-anthracenemethanol (10 g, 48 mmol) and 4-nitrophenyl chloroformate (13.6 g, 67.5 mmol) in 200 ml CH2Cl2 was added triethylamine (6.7 ml, 0.19 mol). The resulting gold colored solution was allowed to stir 16 hrs at room temperature. At this point, 2-(2-aminoethoxy)ethanol (14.4 ml, 0.144 mol) was added and stirring continued for another 24 hours. The CH2Cl2 reaction mixture was then washed with a 2% sodium hydroxide (w/w) solution until no p-nitrophenol was observed in the organic layer. The dichloromethane was dried with sodium sulfate, filtered, and evaporated under reduced pressure.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:12][CH2:13][CH2:14][O:15][C:16]([C:18]1[CH:19]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=2)[C:20]([C:26]([O:28][CH3:29])=[O:27])=[C:21]([CH3:25])[NH:22][C:23]=1[CH3:24])=[O:17].O>CN(C)C=O>[C:1]([S:3][CH2:12][CH2:13][CH2:14][O:15][C:16]([C:18]1[CH:19]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=2)[C:20]([C:26]([O:28][CH3:29])=[O:27])=[C:21]([CH3:25])[NH:22][C:23]=1[CH3:24])=[O:17])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCSC(C)=O)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
To a solution of 0.30 g of thioacetic acid in 20 ml of N,N-dimethylformamide cooled on ice was added 0.50 g of potassium carbonate, and the mixture was stirred for 10 minutes. Then, 0.90 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(3-bromopropyl) ester was added , and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine successively,m and dried over magnesium sulfate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[C:41]([F:52])([F:51])[F:40])=[CH:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccccc1C(F)(F)F)n2S(=O)(=O)c1ccccc1
Yield: 80.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 31, 350 mg, 0.62 mmol), 4-(trifluoromethyl)phenylboronic acid (293 mg, 1.54 mmol) and dichlorobis(triphenylphosphine)palladium (II) (43 mg, 0.06 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 0.8 mL, 1.6 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-methoxy-2-[2-(tetrahydro-pyran-4-yl)-1-(trifluoromethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (272 mg, 82%) as a light yellow solid: LC/MS m/e calcd for C28H25F3N2O4S [M+H]+ 543.58, observed 543.2.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]=[CH:6][CH:7]([N:18]([CH3:35])[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)C.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:35][N:18]([CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH:6]=[CH:5][C:4]([OH:36])=[O:3])[C:19](=[O:34])[C:20]1[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1
Reactant: CCOC(=O)C=CC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)Cc1c[nH]c2ccccc12

Procedure:
A solution of 8.5 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pent-2-enoic acid ethyl ester and 1.2 g of lithium hydroxide in 70 ml of tetrahydrofuran/methanol/water=2/2/1 is stirred at room temperature for 16 hours and then concentrated by evaporation. The residue is dissolved in 150 ml of water with heating to 50°, extracted with ether at 20°, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ether. The combined organic phases originating from the extraction of the acidic aqueous phase are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([Br:49])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN(C)C(=O)C>[Br:49][C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=2)=[CH:48][C:31]=1[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:46][CH2:47]3)=[O:44])[N:41]=2)[N:38]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(Br)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 84.1 %

Procedure:
Using 3-(1-cyano-1-methylethyl)benzoic acid (330 mg, 1.8 mmol), oxalyl chloride (170 μL, 2.0 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (15 mL), N-[6-(5-amino-2-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (650 mg, 1.7 mmol) and N,N-dimethylacetamide (5.0 mL) as starting materials and in the same manner as in Example 335, the title compound (800 mg, 85%) was obtained as a white powder.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]([O:7][CH2:8][C@@H:9]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:10][C:11](=[O:14])[NH:12][CH3:13])=[O:6].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Br-:1].[CH3:13][NH:12][C:11]([O:10][C@H:9]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:8][O:7][C:5]([O:4][CH2:3][CH2:2][N+:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])=[O:14]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)OCCBr)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)OCC[n+]1ccccc1)OC(=O)NC
Product: [Br-]

Procedure:
A solution of 0.15 g of (R)-1-O-[(2-bromoethoxy) carbonyl]-2-O-(methylcarbamoyl)-3-O-octadecylglycerine in 5 ml of pyridine is heated at 60° C. for 20 hours. The solution is evaporated and the residue is treated with toluene by azeotropic distillation. The residue is recrystallized from acetone. There is obtained 1-[2-[[[(R)-2-[(methylcarbamyl)oxy]-3-(octadecyloxy)propoxy]carbonyl] oxy]ethyl]pyridinium bromide of melting point 94° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]12[CH2:28][CH2:27][C:22]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:21][CH:9]1[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([CH:19]=O)[N:16]=[CH:15][C:14]=12.C1COCC1.[Li+].C[Si]([N-:39][Si](C)(C)C)(C)C.[F:44][C:45]1[CH:50]=[CH:49][C:48]([Mg]Br)=[CH:47][CH:46]=1>CCOC(C)=O.O>[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH:19]([C:17]2[N:16]=[CH:15][C:14]3[C@:8]4([CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:28][CH2:27][C:22]5([O:26][CH2:25][CH2:24][O:23]5)[CH2:21][C@H:9]4[CH2:10][CH2:11][CH2:12][C:13]=3[CH:18]=2)[NH2:39])=[CH:47][CH:46]=1
Reactant: O=Cc1cc2c(cn1)C1(Cc3ccccn3)CCC3(CC1CCC2)OCCO3
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(c1ccc(F)cc1)c1cc2c(cn1)[C@]1(Cc3ccccn3)CCC3(C[C@H]1CCC2)OCCO3
Temperature: -5 °C
Reaction time: 1 h
Yield: 105.5 %

Procedure:
A flask with thermometer, septum, nitrogen line and stir bar was charged with rac-(7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolane]-3-carb aldehyde (146, R2=Pyridin-2-ylmethyl) (0.5 g, 1.321 mmol) and THF (15 mL). The mixture was cooled to about −5° C. then LiHMDS (1 M in THF) (1.717 mL, 1.717 mmol) was added. The mixture was stirred at about −5° C. for about 30 min then (4-fluorophenyl)magnesium bromide (2 M in Et2O) (1.321 mL, 2.64 mmol) was added. After about 1 h and 15 min water (2 mL) was added and the mixture stirred for about 15 min. The reaction mixture was diluted with EtOAc (25 mL) and water (˜10 mL). The layers were separated then EtOAc (15 mL) and sat. aq. NH4Cl (˜7 mL) were added to the aqueous layer. The layers were separated then the combined organic solutions were dried over Na2SO4, filtered and concentrated under reduced pressure to yield crude rac-(4-fluorophenyl)((7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-yl)methanamine (147, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.66 g, 105%) which was used directly in the Step 13 without further manipulation; LC/MS, method 3, Rt=1.67 min, MS m/z 474 (M+H)+.