Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1cn3c(c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3n1)N1CCC(C)(CC1)OCC=CC[C@H](C)O2
Yield: 60 %

Procedure:
Prepared from methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate in 60% yield following the same procedure as (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.36-7.28 (m, 2H), 7.18-7.13 (m, 2H), 7.12-7.07 (m, 1H), 6.17-6.06 (m, 1H), 5.92 (br. s., 1H), 5.77 (d, J=15.9 Hz, 1H), 4.57 (br. s., 1H), 4.05-3.90 (m, 3H), 3.64 (t, J=11.0 Hz, 1H), 3.13 (br. s., 1H), 2.64 (d, J=10.7 Hz, 1H), 2.58-2.53 (m, 1H), 2.41 (s, 3H), 2.30 (s, 3H), 2.28-2.20 (m, 1H), 1.96 (d, J=13.1 Hz, 1H), 1.88 (d, J=13.4 Hz, 1H), 1.72 (br. s., 2H), 1.26 (s, 3H), 1.19 (s, 9H), 1.02 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 638.5.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:24])[CH2:16]2)=[O:14])=[CH:11][C:10]=1[C:28]([F:31])([F:30])[F:29])C1C=CC=CC=1>O1CCCC1.CO.[OH-].[Pd+2].[OH-].[C]>[OH:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:24])[CH2:16]2)=[O:14])=[CH:11][C:10]=1[C:28]([F:30])([F:31])[F:29]
Reactant: O=C(c1ccc(OCc2ccccc2)c(C(F)(F)F)c1)N1CS(=O)(=O)c2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ccc(O)c(C(F)(F)F)c1)N1CS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.5 %

Procedure:
3-(4-benzyloxy-3-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (490 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and 20% palladium hydroxide-carbon (100 mg) was added to the solution, and then the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After the reaction solution was filtered, the solvent was distilled off under reduced pressure and then the obtained residue was crystallized from diethylether to obtain the title compound (397 mg) as a colorless crystal.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CS(C)=O>[C:1]1([C:7]2([O:13][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(C2(Oc3ccccn3)CCNCC2)cc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A solution of 4-phenyl-4-piperidinol (7.1 g, 40 mM) in dry DMSO (50 ml) was treated with a 50% sodium hydride dispersion (2.0 g, 40 mM) and the mixture warmed to 80°, until a clear solution was obtained. The solution was cooled to room temperature and treated with a solution of 2-fluoropyridine (3.9 g, 40 mM) in DMSO (10 ml). After 24 hours the reaction mixture was poured onto water (250 ml) and extracted with toluene (3×250 ml). After washing with brine, the organic phase was dried (MgSO4) and the solvents removed under reduced pressure. Recrystallisation from IPE gave the title compound (3.5 g) contaminated with traces of 4-phenyl-4-piperidinol. Fractional crystallisation from cyclohexane gave the title compound analytically pure and chromatographically homogenous (600 mg) m.p. 86°-7°.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:19]=[C:20]4[C:25]=3[CH:24]=[CH:23][CH:22]=[C:21]4[C:26]([F:29])([F:28])[F:27])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.C(N1C(C2C=CC(OCC3C=CC(C(O)=O)=CC=3)=CC=2)=C2C(C(C(F)(F)F)=CC=C2)=N1)C1C=CC=CC=1>>[CH2:30]([N:18]1[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:37])=[O:2])=[CH:5][CH:6]=3)=[CH:12][CH:13]=2)=[C:25]2[C:20]([C:21]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:23]=[CH:24]2)=[N:19]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1
Agent: O=C(O)c1ccc(COc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1
Product: O=C(O)c1ccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1

Procedure:
This compound was prepared from 4-[4-(2-benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenoxy]-benzoic acid methyl ester in a way described for the preparation of 4-[4-(2-benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenoxymethyl]-benzoic acid (Example 2).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[NH2:6][CH:7]([C:12]([OH:14])=[O:13])CCSC.[O-2].[Ca+2:16].[Ca]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[NH2:6][CH2:7][C:12]([O-:14])=[O:13].[Ca+2:16]
Reactant: CSCCC(N)C(=O)O
Reactant: NCC(=O)O
Agent: [Ca+2]
Agent: [Ca]
Agent: [O-2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
About 7.00 grams of water used to dissolve 86.5 grams of glycine and 70 grams of DL-methionine. Next, 47 grams of calcium oxide, which was 70% calcium by weight, was added. The solution was continually stirred until all of the calcium oxide appeared to be dissolved. The reaction formed a calcium bisglycinate chelate or complex solution.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.Cl>CO>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12
Reactant: CC(C)N1CCn2c(CC3(c4ccccc4)CCCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: Cl
Solvent: CO
Product: CC(C)N1CCn2c(CC3(c4ccccc4)CCCCC3)nc(=O)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To the stirred solution of 9-benzyloxy-2-isopropyl-6-(1-phenyl-cyclohexylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (259) (0.18 g, 0.37 mmol) in methanol (5.0 mL) was added concentrated HCl (5.0 mL) and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was reduced and the crude product was extracted with 10% methanol in dichloromethane. The organic part was washed with saturated NaHCO3 solution, separated and dried over Na2SO4. After evaporation, the crude product was purified by nor mal silica gel column chromatography (using 3% methanol in dichloromethane) to get 9-hydroxy-2-isopropyl-6-(1-phenyl-cyclohexylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (260) (70.0 mg, 48.0%) as a white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].Br[CH2:44][CH2:45][O:46][CH3:47]>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:44][CH2:45][O:46][CH3:47])[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: COCCBr
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (90 mg, 0.155 mmol) was dissolved in DMF (1 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 8 mg, 0.20 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then 1-bromo-2-methoxyethane (22 μl, 0.23 mmol) was added. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to afford 51 mg (52%) of 2-[6-chloro-1-(2-methoxy-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow foam.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1O.C(=O)=O>S([O-])([O-])(=O)=O.[Cu+2]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1
Reactant: OC1CCc2ccccc2O1
Agent: [Cu+2]
Agent: O=C=O
Agent: O=S(=O)([O-])[O-]
Product: C1=Cc2ccccc2OC1

Procedure:
In 50 cc of anhydrous ether was dissolved 3.06 g (0.01 mole) of the chromanone compound obtained in Example 32, represented by the following formula: ##STR163## and the solution was cooled to 0° C. and Grignard reagent CH3MgI (0.012 mole) newly prepared in 50 cc of anhydrous ether was dropped into the solution over a period of about 1 hour. After termination of the dropwise addition, the mixture was stirred at room temperature for 2 hours and quietly poured into cold water to extract the product with ether. The ether extract was dried on magnesium sulfate to form a chromanol compound from the chromanone compound. Then, the chromanol compound was heated at 200° C. together with anhydrous copper sulfate in a carbon dioxide current for about 10 minutes. The obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 2.47 g of a chromene compound represented by the following formula: ##STR164##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:37]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@@H:38]([OH:45])[CH2:39][C:40]([O:42]CC)=[O:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:37]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@@H:38]([OH:45])[CH2:39][C:40]([OH:42])=[O:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.8 %

Procedure:
112 mg (0.17 mmole) of ethyl 4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanoate (prepared as described in Example 1) were dissolved in 3 ml of methanol, and 0.2 ml (0.2 mmole) of a 1N aqueous solution of sodium hydroxide was added to the resulting solution. The mixture was then stirred at room temperature for 6 hours, after which it was neutralized by the addition of 1N aqueous hydrochloric acid. The solvent was then removed from the resulting solution by distillation under reduced pressure. To the solid residue were added 5 ml of water and 2 ml of ethyl acetate to form a precipitate, which was crushed and separated by filtration. The resulting residue was washed with water and with a small amount of ethyl acetate, and then dried to give 49 mg of the title compound as a white powder, melting at 191°-192° C., [α]24 -59.2° (C=0.3, methanol).
Reaction SMILES: [C:1]1([N:7]([C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:18][CH3:19])[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH2:26][CH2:27]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([N:7]([C@H:12]2[CH2:17][CH2:16][N:15]([CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:27])[CH2:14][C@H:13]2[O:18][CH3:19])[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCc1ccccc1
Reactant: CCC(=O)N(c1ccccc1)[C@H]1CCNC[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)[C@H]1CCN(C(C)c2ccccc2)C[C@H]1OC
Yield: 61.8 %

Procedure:
cis-N-Phenyl-N-(3-methoxy-4-piperidinyl)propanamide (8, 0.5g, 1.9 mmol) from Example 6, phenylethyl bromide (0.40g, 2.2 mmol) and 2.76g (I9 mmol) of potassium carbonate in 100ml of acetonitrile were heated to reflux overnight. The reaction solution was concentrated under vacuum and the crude residue was purified by chromatography (silica gel; ethyl acetate) to yield 0.43g (62%, Rf 0.326) of pure cis-N-phenyl-N-(1-phenylethyl-3-methoxy-4-piperidinyl) propanamide (I).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([O:8][C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]1)=O.[CH2:37]1COCC1>C1(C)C=CC=CC=1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[C:5]([C:6]([O:8][C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)=[CH2:37])[CH:4]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Reactant: C1CCOC1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: Cc1ccccc1
Product: C=C(O[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 500 mL 3-neck round bottom flask equipped with septa, magnetic stir bar thermocouple, addition funnel and nitrogen line was placed a solution of tert-butyl (3R,4S)-3-{[3,5-bis(trifluoromethyl)benzoyl]oxy}-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (product step A, 17.77 mmol) in 115 mL anhydrous THF. The solution was cooled to 0° C. with an ice/water bath. To the cooled solution was slowly added 45 mL (21.32 mmol) of a 0.5M solution of Tebbe reagent in toluene (commercially available) dropwise by addition funnel. After the addition was complete the funnel was rinsed with anhydrous toluene then THF and the resulting solution added to the reaction mixture. After stirring 1.5 h at 0° C., an additional 9.0 mL (4.5 mmol, 0.25 equiv.) of 0.5M solution of Tebbe reagent in toluene was added dropwise by addition funnel. The reaction was stirred an additional 15 min then carefully quenched by addition of 15 mL water drop by drop. The resulting mixture was transferred to a separatory funnel and extracted with ether/EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The residue dissolved in a minimal amount of methylene chloride filtered and the solvent removed under vacuum. The resulting oil was purified by column chromatography on silica gel eluting EtOAc/hexanes gradient (5/95 to 10/90) to afford the title compound as a yellow foam. 1H-NMR (CDCl3): δ: 1.54 (s, 9H), 3.46-4.01 (br. m, 6H), 4.0 (d, 1H), 4.61 (s, 1H), 4.91 (d, 1H), 7.08 (m, 2H), 7.22 (m, 2H), 7.83 (s, 1H), 8.0 (s, 2H)ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH2:33][CH3:34])[CH:23]2[CH2:32][CH2:31][C:26]3(OCC[O:27]3)[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].O.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH2:33][CH3:34])[CH:23]2[CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(=O)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of 5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(1,4-dioxaspiro[4.5]decan-8-yl)amino)-2-methylbenzamide (2.0 g, 4.1 mmol) in acetone: water (14 mL+6 mL) was added PTSA (3.1 g, 16 mmol). The resulting reaction mixture was stirred at 70° C. overnight. On completion, the solvent was removed under reduced pressure and the residue was basified with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried, concentrated under reduced pressure to give the title compound (1.5 g, 83%) which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:13])[CH:5]=1.C[O:16]C(OC)N(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH:13]=[O:16])[CH:5]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-methyl-4-nitro-benzoic acid methyl ester (24.99 g, 128.1 mmol) and N,N-dimethylformamide dimethyl acetal (40.0 mL, 300 mmol) was heated at 140° C. for 22.5 h. After cooling to rt, the reaction mixture was concentrated and the residue was crystallized from MeOH to give a purple solid. This solid was dissolved in THF (500 mL) and water (500 mL), and sodium periodate (62.62 g, 292.8 mmol) was added followed by additional sodium periodate (15.6 g, 72.9 mmol) two hours later. After stirring at rt for an additional 1 h, the reaction mixture was filtered through Celite washing with EtOAc (2 L). The filtrate was washed with saturated NaHCO3 (600 mL) and the organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was passed through a pad of silica gel, washing with CH2Cl2/hexanes (75%-100%). The filtrate was concentrated and dried to give 3-formyl-4-nitro-benzoic acid methyl ester as yellowish solid. MS (EI): cal'd 210.0 (MH+), exp 210.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH2:14][C:11]1[C:12](=[O:13])[N:7]([CH2:6][C:5]2[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:10]=1)[CH3:33]
Reactant: CNC
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 60.8 %

Procedure:
Following the procedure of Example 7, 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a slightly-yellow crystalline powder (yield: 60.8%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:4])=[O:3].[NH2:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1>N1C=CC=CC=1.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:4])=[O:3])=[C:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=1
Reactant: COC(=O)Cc1cc(F)ccc1S(=O)(=O)Cl
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Reaction time: 96 h
Yield: 97.6 %

Procedure:
A solution of methyl (2-chlorosulfonyl-5-fluorophenyl)acetate (Intermediate 85, 0.293 g) and methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.219 g) in pyridine (1 mL) and DCM (3 mL) was left to stand at room temperature for 4 days. The mixture was diluted with DCM, washed with 2M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give methyl (1aRS,7bSR)-5-[4-fluoro-2-(methoxycarbonylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.438 g) as a colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:17]([CH3:18])=[C:16]([N+:19]([O-])=O)[CH:15]=[C:14]([CH2:22][CH3:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[C:14]([CH2:22][CH3:23])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]=1[CH3:18]
Reactant: CCOC(=O)Nc1c(C)c([N+](=O)[O-])cc(CC)c1C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Nc1c(C)c(N)cc(CC)c1C(=O)OCC
Yield: 94.4 %

Procedure:
A solution of ethyl 2-ethoxycarbonylamino-6-ethyl-3-methyl-4-nitro-benzoate (35 mg) in absolute ethanol (80 ml) was hydrogenated over 10% palladium on charcoal at 50 psi. hydrogen on a Parr hydrogenator for 5 hrs. The catalyst was removed by suction filtration through Celite. The filtrate was evaporated to give an oil which was further purified by thick layer chromatography (30% ethyl acetate: pet. ether 30-60) to give ethyl 4-amino-2-ethoxycarbonylamino-6-ethyl-3-methyl-benzoate as a white solid (30 mg). IR (CH2Cl2): 3340, 1700 (br.), 1600 cm-1. H-NMR (CD3OD): 1.00-1.50 (overlapping peaks [3t], 9H, CH3CH2, 2CH3CH2O), 2.00 (s, 3H, CH3), 2.60 (q, 2H, CH2Ar), 4.15 (q, 2H, CH2), 4.30 (q, 2H, CH2), 6.60 (s, 1 H, ArH).