Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][CH:6]=1.[Li]C(CC)C.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[CH3:14][O:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][C:7]=1[B:20]([OH:25])[OH:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOc1ccc(OCOC)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COCOc1ccc(OCOC)c(B(O)O)c1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Cool a solution of 1,4-bis-methoxymethoxy-benzene 5 (12.0 g, 60.6 mmol) in dry THF (250 mL) to −78° C. Add s-BuLi (1.3 M in hexane, 51 mL, 66.6 mmol) dropwise. Stir the reaction for 15 minutes and then add triisopropyl borate (14.2 mL, 60.6 mmol) slowly. Stir the reaction at −78° C. for 1 hour and warm to room temperature. Quench the reaction with 10% HCl and stir for 10 minutes. Extract with EtOAc (2×). Dry combined organic extracts (Na2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SiO2, 20-50% EtOAc/hexanes and then 50% EtOAc/hexanes) to give 2,5-Bis-methoxymethoxy phenylboronic acid 7 (9.73 g, 40.2 mmol, 66%) as a yellow solid. 1H NMR (δ, 400 MHz, CDCl3): 7.50 (d, J=2.0 Hz, 1H), 7.09-7.07 (m, 2H), 5.93 (s, 2H), 5.24 (s, 2H), 5.14 (s, 2H), 3.49 (s, 3H), 3.48 (s, 3H). LRMS calcd. for C10H14BO6: 241.0; found (electrospray, M−1) 241.0.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[S:29][CH3:30])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[S:29]([CH3:30])=[O:39])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CSc1cc(-n2ccccc2=O)ccc1-n1cnc(CNC(=O)c2ccc(Cl)s2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: CS(=O)c1cc(-n2ccccc2=O)ccc1-n1cnc(CNC(=O)c2ccc(Cl)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared above (16 mg, 0.035 mmol) in acetone (1 mL), mCPBA (70%, 12 mg, 0.049 mmol) was added. After being stirred at room temperature for 30 min, the mixture was purified by HPLC to give the sulfoxide (5 mg) and sulfone (3 mg). MS 473.0 and 475.0 (M+H, Cl pattern) for sulfoxide and 489.0 and 491.0 (M+H, Cl pattern) for sulfone.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1)=[O:15]
Reactant: C1CCNCC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCCCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C

Procedure:
To a 10 mL reaction vial containing stir bar were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.060 g, 0.160 mmol), ethanol (1.5 mL), and then piperidine (0.318 mL, 3.21 mmol) via syringe at once. The contents were capped, placed into a heat block, and heated at 120° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL), adjusted to pH 6-7, and stirred for 15 min. The contents were filtered and washed with water. The product was dried in vacuum oven at 50° C. for 5 hr. The product was obtained as 57 mg (82%). LCMS E-S (M+H)=422.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J=6.82 Hz, 6H), 1.53-1.67 (m, 6H), 2.12 (s, 3H), 2.20 (s, 3H), 3.61-3.73 (m, 4H), 4.34 (d, J=5.05 Hz, 2H), 4.91-5.04 (m, 1H), 5.89 (s, 1H), 7.10 (s, 1H), 7.97 (s, 1H), 8.65 (t, J=4.93 Hz, 1H), 11.51 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:26]=[N:25]1>>[CH:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4([C:23]([F:37])([F:36])[F:22])[N:26]=[N:25]4)[CH:28]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)c1cccc(C2(C(F)(F)F)N=N2)c1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)c3cccc(C4(C(F)(F)F)N=N4)c3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 3-[3-(trifluoromethyl)-3H-diaziren-3-yl]benzoic acid (Preparation 197) to afford the title compound as a white solid in 36% yield, 23 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][CH:29]=[C:28]([O:32][CH3:33])[C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:27]=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: COc1cccc(Cl)c1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: COc1cccc(Cl)c1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 4.1 %

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 2-chloro-6-methoxyphenylboronic acid (available from Aldrich Chemical Company, Inc.; 93 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]-6′-methoxy-biphenyl-2-carboxylic acid (5 mg, 4%). 1H NMR (300 MHz, DMSO-d6), δ 12.87 (br s, 1H), 8.53 (d, J=1.7 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.4, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.32-7.41 (m, 2H), 7.10 (dd, J=18.2, 8.0 Hz, 2H), 3.67 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])=[O:18])=[N:5][CH:4]=1.Cl.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:17]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:3]([CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:4][N:5]=1)=[O:18]
Reactant: COc1ccc(F)c(C(=O)c2ncc(CN)c3cc(OC)c(OC)cc23)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(F)c(C(=O)c2ncc(CNS(C)(=O)=O)c3cc(OC)c(OC)cc23)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
(4-Aminomethyl-6,7-dimethoxy-isoquinolin-1-yl)-(2-fluoro-5-methoxy-phenyl)-methanone (Example 27) (100.5 mg, 0.2269 mmol) was suspended in 5 ml of methylene chloride. The solution was cooled to −78° C. and methanesulfonyl chloride (0.0195 ml, 1.10 eq) was added followed by the addition of N,N-diisopropylethylamine (0.122 ml, 3.0 eq). The mixture was stirred at −78° C. for 1 hr and then at room temperature overnight. The mixture was evaporated and the residue was purified through a flash column chromatography using ethyl acetate and hexane (4/1 ratio) to give N-[1-(2-Fluoro-5-methoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-methanesulfonamide (70 mg, 69%). ES-MS calcd for C21H21N21O6S (m/e) 448.47, obsd 449.0 (M+H).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.O>C(O)(=O)C>[N:4]1([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]#[N:9])[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1ccccc1N
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccccc1-n1cccc1

Procedure:
Anthranilonitrile (10.0 grams, 85.0 mmol) was dissolved in 350 mL of acetic acid. To this was added 2,5-dimethoxytetrahydrofuran (11.0 mL, 85.0 mmol). This was stirred at reflux for 2 hours after which time the reaction mixture was pored into water and the product extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and chromatographed on a silica gel column using a mobile phase of 1:1 dichloromethane-hexane to afford the title compound as a white solid. NMR confirms structure.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([CH2:14][C:15](=[O:20])[CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:3]1>C(O)=O>[F:21][C:2]1([F:1])[CH2:6][NH:5][C@H:4]([CH2:14][C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[CH3:19])[CH2:3]1
Reactant: CC(C)=CC(=O)C[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: O=CO
Product: CC(C)=CC(=O)C[C@@H]1CC(F)(F)CN1

Procedure:
A HCO2H (20 ml) solution of (R)-tert-butyl 4,4-difluoro-2-(4-methyl-2-oxopent-3-enyl)pyrrolidine-1-carboxylate (1.10 g, 3.6 mmol) was stirred at room temperature for 6 hours until only trace amount of SM was detected by LC-MS. Solvent was removed in vacuo with bath temperature ≦23° C. Compound 1-((R)-4,4-difluoropyrrolidin-2-yl)-4-methylpent-3-en-2-one was obtained as a light brown oil and was used directly in next reaction.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=2)O1>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:20]1[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Clc1ccc2ccccc2n1
Product: N#Cc1ccc(-c2ccc3ccccc3n2)cn1
Yield: 2.6 %

Procedure:
A from 2-chloroquinoline (82 mg, 0.5 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (115 mg, 0.5 mmol). The product was obtained as yellow solid (3 mg, 3%). 1H NMR (400 MHz, CDCl3): δ 9.48 (dd, J=2.4, 0.8 Hz, 1H), 8.69 (dd, J=8.0, 2.0 Hz, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.90 (dd, J=8.4, 1.2 Hz, 1H), 7.87 (dd, J=8.4, 0.8 Hz, 1H), 7.81 (m, 1H), 7.63 (m, 1H); MS (ESI):232 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][PH:17](=[O:21])[O:18][CH2:19][CH3:20]>C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]([P:17]([CH3:16])(=[O:21])[O:18][CH2:19][CH3:20])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CCO[PH](C)=O
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)C(O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5.18 g of 3-(benzyloxycarbonylamino)propionaldehyde, 2.7 g of ethyl P-methylphosphinate and 2,53 g of triethylamine is heated to 100° under an inert gas atmosphere for 2 hours. After cooling to room temperature the volatile materials are removed under reduced pressure to afford a viscous oil. Chromatography thereof on silica gel gives ethyl P-(3-benzyloxycarbonylamino-1-hydroxy-propyl)-P-methyl-phosphinate as a colourless, viscous oil.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Cl:9][CH2:10][C:11](=O)[CH3:12]>>[Cl:9][CH2:10][C:11]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: CC(=O)CCl
Product: CC1(CCl)Oc2ccccc2O1
Temperature: 50 °C

Procedure:
110 g (1 mol) of pyrocatechol and 200 ml of chloroacetone were mixed and heated to 50° C. 284 g (2 mol) of phosphoruspentoxide were then added in batches upon strong stirring. The temperature inside the reaction must not exceed 70° C. The mass was then subjected to another hour of stirring whereupon it was decanted and the residue was washed twice with benzene whereupon the united phases were concentrated by evaporation in a rotary evaporator. The mass was then subjected to fractionation in a vacuum (12 torr). The fractions in the boiling range between 104° and 150° C. had a weight of 66 g.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:9])[CH:7]=[CH2:8].[O:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1>O>[C:6]([CH:7]1[CH2:8][CH:16]2[O:15][CH:19]1[CH:18]=[CH:17]2)([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9]
Reactant: c1ccoc1
Reactant: C=CC(=O)OCCCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: CCCCOC(=O)C1CC2C=CC1O2
Reaction time: 1 h

Procedure:
3.3 g (0.013 Mol) SnCl4 is added to 64 g (0.5 Mol) butyl acrylate and dissolved with stirring. Then during cooling to 20° to 25° C., 34 g (0.5 Mol) furane is added drop-wise. The exothermic reaction finishes after one hour, after which stirring is continued for one hour at 25° C. and 30 g of water added. The organic phase is separated. First, the unconverted furane is distilled off under a pressure of 10 Torr, and then the residue is distilled under a pressure of 0.02 Torr. The 2-carbobutoxy-7-oxabicyclo(2.2.1)hept-5-ene boils at 65° C. and is obtained in a yield of 34.3 g (35% of the theoretical).
Reaction SMILES: [OH:1][P:2]([OH:5])([OH:4])=[O:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH2:20][C:21]1([CH2:40]O)[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=2)[CH2:22]1>O>[P:2]([OH:5])([OH:4])([O:1][CH2:40][C:21]1([NH2:20])[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:31]=2)[CH2:22]1)=[O:3]
Reactant: O=P(O)(O)O
Reactant: CCCCCCCCc1ccc(C2CCC(N)(CO)C2)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CCCCCCCCc1ccc(C2CCC(N)(COP(=O)(O)O)C2)cc1
Temperature: 100 °C

Procedure:
1 mL of 85% H3PO4 was slowly added (by drops) into 0.5 g of P2O5, the acid-anhydride mixture was then heated at 100° C. for 1 hour under nitrogen protection. Another 0.5 g of P2O5 and 30 mg of alcohol 6 were added to the poly phosphoric acid and heated for 5 hours at 100° C. After cooling down to room temperature, 10 mL cold water (0° C.) was added to reaction mixture. The product precipitated out as white solid, was collected and washed with water. 31 mg (82%) of green colored product was collected after vacuum drying. MS only two peaks: M+1=384.4 with 304.4 (hydrolyzed back to 6).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH2:3]([O:10][N:11]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)CBr
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
Sodium hydride (0.97 g of 80% in mineral oil, 32 mmol) was added to a solution of tert-butyl N-benzyloxycarbamate (6.53 g, 29 mmol) in N,N-dimethylformamide (45 mL). A gas evolved and the mixture was stirred for 20 minutes. Isobutyl bromide (3.5 mL, 32 mmol) was added and the reaction mixture was heated at 70° C. for 1.5 hr. The reaction was quenched with water (about 50 mL) then extracted twice with diethyl ether. The extracts were combined, washed with water (5 small portions), dried over magnesium sulfate and then concentrated under vacuum to provide 7.63 g of tert-butyl N-benzyloxy-N-(2-methylpropyl)carbamate as a faintly brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([O:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([O:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20]/[CH:21]=[N:8]/[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(CC=O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C(=O)OCc1ccccc1
Yield: 93.2 %

Procedure:
Step D In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.72 g, 13.2 mmol) was reacted with 2,2-dimethyl-4-oxo-butyric acid benzyl ester (4.1 g, 132 mmol) in CH2Cl2 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester as a colorless oil (4.1 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][S:4](=[O:11])(=[O:10])[N:5]([CH3:9])[C:6](=O)[N:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:6]1[N:5]([CH3:9])[S:4](=[O:11])(=[O:10])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1=NC(=O)N(C)S(=O)(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NS(=O)(=O)N(C)C(Cl)=N1
Temperature: 110 °C
Yield: 100 %

Procedure:
212 parts of 3,6-dimethyl-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide were introduced into a stirred mixture of 292 parts of phosphorus pentachloride and 1,400 parts of phosphorus oxychloride at room temperature, and the mixture was heated to 110° C. in the course of 30 minutes. The reaction mixture was stirred under reflux for 6 hours and then evaporated down under reduced pressure to give 234 parts (yield: 100% of theory) of 5-chloro-3,6-dimethyl-6H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 86°-90° C. NMR (60 MHz, CDCl3): CH3 --C 2.4δ, CH3 --N 3.68).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[C:18]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH:17]=1)[O:10][C:11](=[O:15])[CH2:12][CH2:13][OH:14].[C:33]([O:37][C:38]([N:40]([C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][C:46]=1[O:54][CH2:55][CH:56]1[CH2:58][CH2:57]1)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:33]([O:37][C:38]([N:40]([C:45]1[CH:53]=[CH:52][C:48]([C:49]([O:14][CH2:13][CH2:12][C:11]([O:10][C@H:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[C:18]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:17]=2)[CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N+:4]([O-:32])=[CH:5][C:6]=2[Cl:31])=[O:15])=[O:50])=[CH:47][C:46]=1[O:54][CH2:55][CH:56]1[CH2:57][CH2:58]1)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(CCO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-hydroxypropanoyloxy)ethyl)pyridine 1-oxide (0.311 g, 0.632 mmol), 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoic acid (0.243 g, 0.632 mmol), and EDC (0.363 g, 1.895 mmol) in dry DCM (15 ml), DMAP (0.077 g, 0.632 mmol) was added and the resulting mixture was stirred at RT for 3 hours. The solvent was evaporated, and the residue was partitioned between EtOAc and a NaHCO3 sat. sol. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel column (DCM:MeOH:32% NH4OH=95:5:0.5) affording (S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)-methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.450 g, 0.523 mmol, 83% yield, MS/ESI+ 859.0 [MH]+).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10]O)[CH3:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([CH2:3][C:4]([O:6][CH2:10][CH:9]([CH2:7][CH3:8])[CH2:12][CH2:13][CH2:14][CH3:15])=[O:5])#[N:2]
Reactant: CCCCC(CC)CO
Reactant: N#CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCC(CC)COC(=O)CC#N
Temperature: 110 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a 1000 ml four neck flask fitted with mechanical agitator, thermometer, Dean and Stark apparatus and water condenser, add 237.5 g (2.23 mol on pure substance) 80 wt.-% cyanoacetic acid in water, 440 g (3.38 mol) 2-ethylhexanol and 1.2 g (6.3 mmol) p-toluenesulfonic acid monohydrate. Afterwards, the mixture is heated to reflux (110° C.) under atmospheric pressure for 1 hour and the water (both initial and formed) is azeotropically distilled out using a Dean and Stark apparatus returning the upper organic layer to the reactor. After 1 hour and at a temperature of 130° C. gradually a vacuum of 400 mbar is applied using a water respirator. The azeotropic distillation is maintained for further 6 hours while gradually increasing the vacuum from 400 mbar to 30 mbar in order to maintain a temperature of 130° C. until no further water is removed. After releasing the vacuum the reaction mixture is cooled to 90° C. After the addition of about 100 ml water (pre heated to 90° C.), the mixture is stirred at 85-90° C. for 10 minutes before separation of the phases. The upper organic layer is transferred to a 1000 ml four neck flask fitted with mechanical agitator, thermometer, packed column (ID=30 mm, H=1200 mm, packing metal raschid rings D=7 mm), water condenser and distillate flasks. Excess 2-Ethylhexanol is distilled out at 130-140° C. under a vacuum of 10-30 mbar. When complete increase the vacuum to 1.5 mbar and distilled out 2-ethylhexyl cyanoacetate at 130-140° C. 2-Ethylhexyl cyanoacetate is obtained as a colourless liquid. The reaction yield is 92% (based on cyanoacetic acid).