Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH:16]=[CH2:17])=[CH:5][CH:4]=1.[O:18]=[C:19]1[CH2:23][N:22]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[C@H:21]([C:33]([O:35][CH3:36])=[O:34])[CH2:20]1>C1COCC1.C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([CH:16]=[CH2:17])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C@@:19]3([OH:18])[CH2:23][N:22]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])=[O:25])[C@H:21]([C:33]([O:35][CH3:36])=[O:34])[CH2:20]3)=[CH:4][CH:5]=2)[CH:14]=1
Reactant: C=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1ccc(Cl)cc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Magnesium (0.298 g, 12.27 mmol) was stirred in a round bottom flask under nitrogen for 15 min. to cause scratching of the surface of the magnesium turnings. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 4′-bromo-5-chloro-2-vinylbiphenyl (3.43 g, 11.68 mmol) in THF (60 mL), was added in dropwise at reflux with vigorous stirring. The Grignard solution was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (3.35 g, 11.67 mmol) in DCM (60 mL) at r.t. and stirred for 1 hr and then quenched with saturated NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (800 mg, 1.593 mmol, 14% yield) as a yellow oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 9H) 1.03 (dd, j=9.46, 7.63 Hz, 2H) 2.30-2.48 (m, 1H) 2.63-2.79 (m, 1H) 3.77-3.80 (m, 1H) 3.82-3.86 (m, 3H) 3.95-4.05 (m, 1H) 4.16-4.26 (m, 2H) 4.51-4.67 (m, 1H) 5.20 (d, J=11.90 Hz, 1H) 5.67 (d, J=17.40 Hz, 1H) 6.61 (dd, J=17.40, 10.99 Hz, 1H) 7.26-7.35 (m, 4H) 7.49-7.58 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:22]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Phenylacetic acid (1.09 g, 8.0 mmoles) was dissolved in 5 ml dichloromethane. To this mixture, oxalylchloride (1.01 g, 8.0 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 5 ml dichloromethane. To this mixture, 4-bromoanisole (1 g, 5.34 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (1.06 g, 8.0 mmoles) was added and the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography to afford the title compound as white solid (1 g, 66% yield). MP: 83-86° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 11.56 (s, 1H), 8.01 (d, J=2.2Hz, 1H), 7.64 (dd, J=8.8, 2.5Hz, 1H), 7.32 (t, 2H), 7.29 (m,3H), 6.96 (d, J=8.8Hz, 1H), 4.43(s, 2H).
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)C(C)C)(C)C.Cl[C:29]1[O:30][C:31]2[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:32]=2[N:33]=1.C(OCC)(=O)C>CN(C=O)C>[OH:38][C:36]1[CH:35]=[CH:34][C:32]2[N:33]=[C:29]([N:8]3[CH2:9][CH2:10][CH:5]([O:4][CH2:3][C@@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:1])[CH2:6][CH2:7]3)[O:30][C:31]=2[CH:37]=1
Reactant: Oc1ccc2nc(Cl)oc2c1
Reactant: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
To a solution of tert-butyl [(1S)-1-methyl-2-(piperidin-4-yloxy)ethyl]carbamate (308 mg) and N,N-diisopropylethylamine (0.311 mL) in DMF (2 mL) was added 2-chloro-1,3-benzoxazol-6-ol (202 mg), and the mixture was stirred at room temperature for 5 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The extract was applied to silica gel chromatography (NH, ethyl acetate), and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (446 mg).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([S:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>CCOCC>[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([S:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][Br:2])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(Sc2ccc(CO)cc2)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 183.9 %

Procedure:
To a stirred mixture of phosphorus tribromide (1.20 g, 4.43 mM) and dry ether (100 ml) was added a solution (20 ml) of 4-(4-methylthiophenoxy)benzyl alcohol (3.00 g, 12.1 mM) in dry ether at the room temperature, and the mixture was stirred for 12 h at the same temperature. The mixture was poured into ice water, and the mixture was extracted with ether. The extract was washed with saturated sodium hydrogen carbonate solution and brine, dried with magnesium sulfate, and concentrated in vacuo to give 4-(4-methylthiophenoxy)benzyl bromide (2.39 g, 64%) as colorless crystals, m.p. 32.9° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:13]2[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=2[S:15][C:16]=1[CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[C:13]2[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=2[S:15][C:16]=1[CH2:17][CH2:18][CH:19]=[O:20]
Reactant: OCCCc1sc2ccccc2c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: O=CCCc1sc2ccccc2c1Cl
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
A −78° C. solution of oxalyl chloride (1.73 g, 13.6 mmol) in dichloromethane (20 mL) was treated with DMSO (20 mL). After 5 min., a solution of alcohol 16 (2.57 g, 11.3 mmol) in dichloromethane (20 mL) was added. After another 15 min., triethylamine (7.1 mL, 50.6 mmol) was added. The reaction was stirred at −78° C. for 5 min., and then allowed to warm to room temperature. After 30 min., 100 mL water was added and the mixture extracted with dichloromethane (3×60 mL). The combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (10% ethyl acetate/hexane) gave 2.11 g (9.4 mmol, 83%) of the aldehyde (17).
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([C:25](O)=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1)[CH2:4][F:5].Cl.C(N=C=NCCCN(C)C)C.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][CH2:2][CH:3]([O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([C:25]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1)[CH2:4][F:5]
Reactant: CS(N)(=O)=O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(CF)CF)c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(C(=O)NS(C)(=O)=O)sc2ncnc(Nc3ccc(F)cc3OC(CF)CF)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(2-(1,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (197 mg), 4-dimethylaminopyridine (76 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg) was dissolved in dichloromethane (20 ml). Methanesulfonamide (59.5 mg) was added and the reaction was stirred at room temperature for about 24 h. The mixture was washed with a KHSO4 solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography (dichloromethane: methanol: NH3 80:20:1). The fractions were collected and triturated with diisopropyl ether.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[CH:16][C:6]=1[O:7][CH:8]([CH2:12][C:13](O)=[O:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:34](O)[CH3:35]>O>[C:20]([C:18]1[CH:19]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:7][CH:8]([C:9]([O:11][CH2:34][CH3:35])=[O:10])[CH2:12][C:13](=[O:14])[C:16]=2[CH:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(OC(CC(=O)O)C(=O)O)c(C(C)(C)C)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 50 parts of 2,4-di-t-butylphenoxysuccinic acid and 100 parts of concentrated sulphuric acid was stirred at room temperature for three hours. The resulting solution was poured into water, excess sodium bicarbonate solution was added and the basic solution was extracted with ether. The aqueous extract was acidified with concentrated hydrochloric acid and the product was extracted into ether. The ether extract yielded a residue which was esterified by refluxing for three hours with 200 parts of a 3% v/v solution of ethanol containing sulphuric acid. After cooling, water was added and the esterified product was extracted into ether. The ether extract was washed with sodium bicarbonate solution and water, dried and the ether was removed by evaporation. Chromatography of the resulting residue on silica gel, eluting with a 3:2 mixture of chloroform and light petroleum (b.p. 40°-60°C), gave 1 part of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester as a semi-solid.
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]([C:12]([Br:15])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=O)C.C(=O)([O-])O.[Na+]>CO>[NH2:4][C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]([C:12]([Br:15])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(Br)ccc(N)c1[N+](=O)[O-]
Yield: 100 %

Procedure:
Methyl 3-acetylamino-6-bromo-2-nitrobenzoate (Reference Compound No. 1-(3), 13.4 g, 42.2 mmol) was dissolved in methanol (240 mL), boron trifluoride diethyl etherate complex (24.0 mL, 190 mmol) was added thereto, and then the mixture was refluxed for 2.5 hours. After the reaction mixture was neutralized with sodium hydrogen carbonate (48 g), the mixture was concentrated under reduced pressure. After ethyl acetate (500 mL) and water (700 mL) were added thereto and the mixture was partitioned, the ethyl acetate layer was washed with water (700 mL) and saturated brine (700 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the titled reference compound (11.6 g) as an orange solid. (Yield 100%)
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:12]=1.C(C1C=NC=CC=1)(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:57][CH2:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([O:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[Cl:74])[CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.O>[Cl:74][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=1[O:67][CH:64]1[CH2:63][CH2:62][N:61]([C:59](=[O:60])[CH2:58][NH:57][C:22]([C:19]2[CH:18]=[C:17]([C:13]3[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=3)[NH:21][N:20]=2)=[O:24])[CH2:66][CH2:65]1
Reactant: O=C(O)c1cc(-c2cccnc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CC(=O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2cccnc2)[nH]n1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
DIPEA (290 mg, 2.26 mmol) to a stirred solution of 5-pyridin-3-yl-1H-pyrazole-3-carboxylic acid hydrochloride (100 mg, 0.44 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 3-acetylpyridine) in DMF (2 mL) followed by HOBt (63 mg, 0.46 mmol) and EDCI.HCl (90 mg, 0.46 mmol). After 2 minutes 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (150 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from 10% EtOAc in hexane afforded 100 mg (51.5% Yield) of 5-pyridin-3-yl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440, 96.47%. 1H NMR (300 MHz, DMSO-d6): δ 13.9 (s, 1H), 9.0 (m, 1H), 8.5 (m, 1H), 8.1 (m, 2H), 7.4 (m, 2H), 7.2 (m, 3H), 6.9 (m, 1H), 4.75 (m, 1H), 4.2 (m, 2H), 3.65 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH:23]([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])[C:19]([N+:32]([O-:34])=[O:33])=[C:18]([F:35])[CH:17]=2)[CH2:11][S:10](=[O:37])(=[O:36])[CH2:9]1)(C)(C)C.[ClH:39]>C1COCC1.O1CCOCC1>[ClH:39].[NH2:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH:23]([C:24]([F:27])([F:26])[F:25])[C:28]([F:31])([F:29])[F:30])[C:19]([N+:32]([O-:34])=[O:33])=[C:18]([F:35])[CH:17]=2)[CH2:11][S:10](=[O:36])(=[O:37])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OC(C(F)(F)F)C(F)(F)F)c2)[C@@H]1O
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OC(C(F)(F)F)C(F)(F)F)c2)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {(3R,4S,5S)-5-[3-fluoro-4-nitro-5-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-benzyl]-4-hydroxy-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-3-yl}-carbamic acid tert-butyl ester (3.42 g, 5.85 mmol) in THF (5 mL) was added 4N HCl in dioxane (20 mL) and the reaction mixture was stirred for 2 h at 25° C. After evaporation the residue was stirred with Et2O, filtered and dried to provide the title compound as a beige solid: TLC (EtOAc-MeOH 9:1) Rf=0.12; HPLC RtA=1.76 min; ESIMS [M+H]+=485; 1H NMR (400 MHz, CD3OD): δ 7.24 (s, 1H), 7.18 (d, 1H), 6.29 (m, 1H), 3.3-3.7 (m, 5H), 3.21 (dd, 1H), 2.97 (m, 1H), 2.70 (dd, 1H), 2.42 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:30])=[C:6]([C:26]([F:29])=[CH:27][CH:28]=1)[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:16](O)=[O:17])[C:12](=[O:14])[CH:13]=1)[CH3:2].[CH3:31][C:32]1([CH3:44])[O:36][C@H:35]([CH2:37][N:38]2[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]2)[CH2:34][O:33]1>>[CH3:31][C:32]1([CH3:44])[O:36][C@H:35]([CH2:37][N:38]2[CH:42]=[CH:41][C:40]([NH:43][C:16](=[O:17])[CH:15]([N:11]3[C:12](=[O:14])[CH:13]=[C:8]([O:7][C:6]4[C:26]([F:29])=[CH:27][CH:28]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:30])[CH:9]=[N:10]3)[CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:39]2)[CH2:34][O:33]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCOc1ccc(F)c(Oc2cnn(C(CC3CCOCC3)C(=O)O)c(=O)c2)c1F
Product: CCOc1ccc(F)c(Oc2cnn(C(CC3CCOCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1F

Procedure:
Using the method described in Example 49, 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 93) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as an off-white solid as a mixture of diastereoisomers (138 mg, 55%).
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.NC[CH2:19][CH2:20][C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:7]1(=[O:16])[N:6]([CH2:1][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: NCCCC(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O
Yield: 63 %

Procedure:
N-Carboethoxyphthalimide (10.96 g) was added in one portion to a vigorously stirred solution of 4-aminobutanoic acid (5.16 g) and sodium carbonate (5.35 g) in water (150 ml) at RT. The mixture was stirred until essentially all the solid material had dissolved (30 min), then it was filtered. The filtrate was acidified to pH1 with 6 N aqueous hydrochloric acid (ca. 22 ml) and the white precipitate was collected by filtration and washed thoroughly with water (150 ml). The solid was dried in air, then in vacuo to give the title compound as a colourless solid (7.35 g).
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[N:15][CH:16]=1)([O-:10])=[O:9]>ClCCl>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:15][CH:16]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (5 eq) was added to a solution of tert-butyl 4-(5-nitropyridin-2-yloxy)piperidine-1-carboxylate (1 eq) in dichloromethane, stirring at room temperature for 1 hour. The solvent was then evaporated, the residue brought to pH=10 with sat. aq. Na2CO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford the product as a light yellow crystalline solid. LC/MS (m/z): 224.3 (MH+), Rt 1.64 minutes
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[OH-].[Na+]>FC(F)(F)C(O)=O.CCOCC.O=[Pt]=O>[NH:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CC2CCCCC2N1

Procedure:
Dissolve 27.0 g of ethyl indole-2-carboxylate in 250 ml of trifluoroacetic acid. Add 2.05 g of platinium oxide, hydrogenate the mixture at 50 lb/in2 at room temperature. Filter the mixture and concentrate the filtrate in vacuo to give a residue. Suspend the residue in ether and treat with cold dilute sodium hydroxide solution. Dry the organic layer over magnesium sulfate and concentrate it to give ethyl octahydroindole-2-carboxylate, a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](OC)(OC)OC.OS(O)(=O)=O>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(F)c(O)c1
Temperature: 47.5 °C

Procedure:
4-Fluoro-3-hydroxybenzoic acid (20.0 g, 0.13 mol) was dissolved in anhydrous methanol (160 mL), mixed with trimethyl orthoformate (25 mL) followed by the addition of concentrated H2SO4 (3 mL) and the reaction was heated to 40-55° C. overnight. Half of the solvent was removed in vacuo, the remaining solution was poured into an ice/H2O mixture and the product was extracted twice with diethyl ether. The combined ether phases were washed twice with H2O, treated with a cold solution of saturated NaHCO3, treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give 21.6 g (99% yield) of a white solid as the title compound (mp 93.5-94.5° C.). Mass spectrum (70 eV) m/z (relative intensity) 170 (44, M+), 139 (100), 111 (83), 83 (83), 82 (16), 81 (11), 63 (11), 57 (24).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]([CH3:17])[CH2:13][CH:12]=1.[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH2:29].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH:28]([C:2]1[CH:3]=[C:4]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)=[CH2:29]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CN1C=CC(c2c[nH]c3c(Br)cc(OS(=O)(=O)c4ccccc4)cc23)=CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1cc(OS(=O)(=O)c2ccccc2)cc2c(C3CCN(C)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of benzenesulfonic acid 7-bromo-3-(1-methylpyridin-4-yl)-1H-indol-5-yl ester and Pd (PPh3)4 (0.2 eq.) in dry toluene was degassed and then treated with vinyl tributyltin (1.1 eq.). Heat the reaction mixture to reflux. After 5 hours, cool to room temperature, pour into ethyl acetate, wash with brine, dry the organic layer over Na2SO4, and concentrate. Purify to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23]C)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[CH3:22][O:21][C:19]1[CH:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=[C:17]([OH:23])[N:18]=1
Reactant: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(OC)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(NC2CCNCC2)nc(O)n1

Procedure:
A solution of 4-(2,6-dimethoxy-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.71 g, 2.10 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 225.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.C[Si]([N:37]=[C:38]=[O:39])(C)C>>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][C:38]([NH2:37])=[O:39])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(C#CC(C)(C)NC(N)=O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and trimethylsilyl isocyanate. LC-MS Method 1 tR=1.43 min, m/z=463; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.47 (d, 3H), 1.67 (s, 6H), 2.10-2.30 (4H), 2.38 (m, 1H), 2.77 (m, 1H), 5.58 (q, 1H), 6.78 (d, 1H), 7.08 (d, 1H), 7.30-7.40 (5H).