Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][N:36]([CH3:41])[CH3:35])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 16.2 %

Procedure:
4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 459 mg, 1 mmol), N,N-dimethylglycine (206 mg, 2 mmol), and triethylamine (0.278 mL, 2 mmol) were stirred in dry DMF (5 mL) and then HATU (760 mg, 2 mmol) was added portionwise. The reaction mixture was heated at 70° C. for 40 mins then a further quantity of HATU (760 mg, 2 mmol) was added and the mixture heated at 80° C. for 1 hr. The reaction mixture was allowed to cool and then partitioned between EtOAc and water. The organic layer was washed with water followed by brine, and then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was treated with DCM, the suspension filtered and the filtrate purified by flash chromatography with a gradient of 0-10% MeOH in DCM to afford the title compound as a white solid (88 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:18]>CN(C)C=O>[Br:1][C:2]1[C:7](=[O:18])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1
Reactant: CCOC(=O)c1c(Cl)cc(Br)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(=O)c(Br)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate (3, 150 g, 534.8 mmol) in dimethylformamide (900 mL) at 0° C. was added trifluoroacetic anhydride (224.63 g, 1.07 mmol). The temperature of the reaction mixture was raised to 50° C. and stirring was continued for 1 h. After the oxidation was complete, the reaction mass was quenched with a saturated aqueous sodium bicarbonate solution and product was extracted with dichloromethane (2×100 mL). The organic layers were separated, combined, dried with magnesium sulfate and concentrated to dryness under vacuum to afford ethyl 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4) as a yellow solid. Yield: 75 g, 50%; MS (ESI) m/z 281.8 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.44-10.02 (m, 1H), 7.86 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 1.43 (t, J=5.6 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([OH:31])[C:19]#[C:20][C:21]([O:24]C2CCCCO2)([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2].Cl.[O:45]1CC[CH2:47][CH2:46]1>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([O:31][C:46](=[O:45])[CH3:47])[CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@H](O)C#CC(C)(C)OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: C1CCOC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@@H](CCC(C)(C)O)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
109 mg of (22S)-1α,3β-diacetoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn-22-ol (IIIa1) was dissolved in a mixture of methanol and tetrahydrofuran, and after adding thereto 3 drops of 2N-hydrochloric acid, the mixture was stirred for 3 hours at room temperature. The reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and water, successively. After drying with magnesium sulfate, the solvent was distilled away. The residue obtained was dissolved in 10 ml of ethyl acetate, and after adding thereto 10 mg of 10% Pd-C, the mixture was stirred for 4 hours at room temperature under an hydrogen stream atmosphere. The catalyst was filtered off, and the mixture was washed with ethyl acetate, and a combined solution of filtrate and washing was concentrated under reduced pressure. The residue was dissolved in 0.5 ml of pyridine, and after adding thereto 0.1 ml of acetic anhydride, the mixture was stirred overnight at room temperature. After adding water to the reaction solution, the mixture was extracted with ethyl acetate. The extract organic layer was washed with 2N-hydrochloric acid, satureated aqueous sodium hydrogen carbonate, and water, successively, and dried over magnesium sulfate. The solvent was distilled away, and the residue was subjected to column chromatography (n-hexane-ethyl acetate=4:1) for purification to give 71.6 mg of (22R)-1α,3β,22-triacetoxycholest-5-en-25-ol (IVa1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(COc2ccc(Br)cc2)C1
Temperature: 110 °C
Yield: 84.7 %

Procedure:
A mixture of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (200 mg, 1.07 mmol), 4-bromophenol (222 mg, 1.28 mmol), triphenylphosphine (368 mg, 1.40 mmol) and DIAD (259 mg, 1.28 mmol) in anhydrous THF (5 mL) was heated to 110° C. under nitrogen for 5 hours. The reaction mixture was concentrate in vacuo to give a brown residue, which was purified by flash chromatography (petroleum ether/ethyl acetate 20:1 to 5:1) to give tert-butyl 3-[(4-bromophenoxy)methyl]azetidine-1-carboxylate (310 mg, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 2H), 6.78 (d, 2H), 4.06 (m, 4H), 3.79 (m, 2H), 2.96 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][N:52]([C:55](=[O:57])[CH3:56])[CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.CCCCCCC>[C:55]([N:52]1[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH:10]=[CH:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:13][CH2:14]3)=[CH:19][CH:20]=2)[CH2:50][CH2:51]1)(=[O:57])[CH3:56]
Reactant: CC(=O)N1CCN(CCO)CC1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 23.5 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Dichloromethane (225.0 mL) and 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (50.0 g, 138 m mol) were charged to a suitable round bottom flask at 22-25° C. Triphenylphosphine (72.2 g, 275 m mol) and 1-[4-(2-hydroxy-ethyl)piperazin-1-yl]ethanone [CAS: 83502-55-0] (47.4 g, 275 m mol) were added successively to the reaction mass and stirred for 10 min at 22-25° C. Di-isopropyl azodicarboxylate (55.65 g, 275 m mol) in dichloromethane (75.0 mL) was added to the reaction mass slowly drop wise at 25-30° C. over a period of 60-90 min. The resulting reaction mass was stirred for 1.0 h at 25-30° C. to complete the reaction. n-Heptane (600.0 mL) was introduced to the reaction mass by drop wise addition over a period of 15-30 min at 22-25° C. and stirred for 30 min at the same temperature. Thus precipitated solid was filtered and washed with n-heptane (150.0 mL). The material was then suck dried for 30 min under reduced pressure. The crude material was purified by slurry washing in methanol (325.0 mL) at 22-25° C. The solid was then collected by filtration and washed with methanol (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (61.2 g, 84%) as a free flowing solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH:9]=[C:10](Br)[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[F:12]
Reactant: COC(=O)c1cc(Br)c(F)c(N)c1OC
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccccc2)c(F)c(N)c1OC
Temperature: 90 °C
Reaction time: 36 h
Yield: 92.1 %

Procedure:
Methyl 3-amino-5-bromo-4-fluoro-2-methoxybenzoate (I-230) (504 mg, 1.81 mmol) was dissolved in 1,4-dioxane (10 ml), then under nitrogen atmosphere at room temperature, phenylboronic acid (456 mg, 3.62 mmol), tripotassium phosphate (770 mg, 3.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.18 mmol) were added. After stirred at 90° C. for 36 hours, this was cooled to room temperature. The insoluble matter was separated by filtration with washing with ethyl acetate, the filtrate was fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=3:1) to obtain the entitled compound (459 mg, 92%) as a colorless gel substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:13])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:13])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2cccnc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2cccnc2C1=O

Procedure:
The mixture of 2.83 g of N-(4-nitro-o-tolyl)-pyridine-2,3-dicarboximide, 200 ml of ethyl acetate and 1.6 g of prewashed Raney nickel is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated, the residue taken up in chloroform, the solution treated with charcoal, filtered, evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-o-tolyl)-pyridine-2,3-dicarboximide of the formula ##STR6## melting at 180°-182°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1>C(O)(C)C>[CH:8]([O:14][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1)([CH3:9])[CH3:7]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C#N
Solvent: CC(C)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1C#N

Procedure:
Similar procedure as described in example 400 was used, starting from isopropyl alcohol and 1-Chloro-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carbonitrile (example 9H) to give 1-Isopropoxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carbonitrile. LC-MS: m/e 338(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]1[S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:18]=1)=[CH:7]2.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:13][O:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:29]([C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)(=[O:31])=[O:30])[CH:7]=[C:8]1[C:14]1[S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:18]=1
Reactant: CCOC(=O)c1cnc(-c2cc3cccc(N)c3n2COC)s1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3n2COC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a mixture of ethyl 2-[7-amino-1-(methoxymethyl)-1H-indol-2-yl]-1,3-thiazole-5-carboxylate (2.18 g) and pyridine (25 mL) was added thiophene-2-sulfonyl chloride (1.50 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (2.19 g, yield 70%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 133-134° C.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH2:22]2)[CH2:13][C@H:9]1[C:10]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:12])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C1CNCCN1
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCNCC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
(4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-L-proline (0.92 g, 2.41 mmol) obtained in Step C of Example 1, was dissolved in DMF (10 mL) and DIPEA (1.05 mL, 6.01 mmol) was added thereto. Piperazine (0.25 g, 2.89 mmol) and HBTU (0.91 g, 2.41 mmol) were also added thereto in order. After the reaction solution was stirred at room temperature for 2 hours, the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution. The extracted organic solution was dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography (eluent: MC/MeOH=10/1) to give the title compound (1.01 g, 93%).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10]>>[CH2:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOC(=O)Cl
Reactant: COP(OC)OC
Product: CCCCOC(=O)P(=O)(OC)OC

Procedure:
From 10.0 ml (85 mmole) of trimethylphosphite and 8.7 g (64 mmole) of n-butyl chloroformate. (100° C., 1.5 hours). Yield 10.9 g (81%). Bp1.0 97°-100° C. nD25 1,4269.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)=[N:5][N:4]=[N:3]1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1nnnc1-c1cccc(N)c1
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
1-Methyl-5-(3-nitrophenyl)-tetrazole (28.8 g, 140 mmol) was dissolved in ethyl acetate (430 mL) and methanol (1270 mL). Palladium on carbon (2.7 g, 10 wt %) was added and the mixture was shaken under a hydrogen atmosphere (60 psig) for 1.5 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to give a white solid (24.0 g, 98%). 1H NMR (300 MHz, CDCl3), δ7.21 (dd, J=8, 7 Hz, 1H) 6.99 (s, 1H), 6.90 (d, J=7 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 5.44 (bs, 2H), 4.10 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])O[C:15]=3[CH3:22])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH3:27]>>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[NH:27][C:15]=3[CH3:22])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)o1
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)[nH]1

Procedure:
3-(4-(4-Trifluoromethylphenoxy)phenyl)-2,6-dimethylpyran-4-one (2-4 g) was heated at 150° with 0.880 aqueous ammonia (30 ml) in an autoclave for 18 hours. After cooling the precipitate was filtered off, washed with water, dried in air and recrystallised from DMF to yield the title compound as fine colourless crystals (1.4 g). M.p. 258°-260°, NMR δH (d6 -DMSO) 7.70 (2H, dd, J 5, 0.5 Hz), 7.0-7.3 (6H, m), 5.97 (1H, s), 2.2 (3H, s), 2.1 (3H, s).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][N:20]=1)=[O:9])=O)C.C(=O)([O-])O.[Na+]>CCCCCC.C(OCC)(=O)C>[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](/[CH:18]=[CH:17]/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]2[C:4](=[O:3])[CH2:5][NH:7][C:8]2=[O:9])=[N:20]1
Reactant: CCOC(=O)C(=O)NC(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CNC(=O)N1c1ccccc1/C=C/c1n[nH]c2ccccc12
Yield: 85.3 %

Procedure:
(E)-(3-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}ureido)oxoacetic acid ethyl ester (50 mg, 0.14 mmol) obtained in Step 1 was heated under reflux in a mixed solvent of 6.0 mol/L hydrochloric acid/acetone (1/1, 2.5 mL) under nitrogen atomosphere for 60 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) to obtain Compound 212 (38 mg, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([CH:13]=[CH2:14])[C:9]1=[O:15])=[O:7])([CH3:4])(C)C.[H-].[Na+].Cl[CH:19]1[CH2:23]CC[O:20]1>O1CCCC1.C(OCC)C>[O:20]1[CH2:19][CH2:23][CH2:4][CH:1]1[O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([CH:13]=[CH2:14])[C:9]1=[O:15])=[O:7]
Reactant: C=CN1CCC(C(=O)OC(C)(C)C)C1=O
Reactant: ClC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CN1CCC(C(=O)OC2CCCO2)C1=O

Procedure:
8.9 g or 3-(t-butoxycarbonyl)-1-vinyl-2-pyrrolidinone (BCVP) was dissolved in 50 ml of tetrahydrofuran free of moisture. To this solution 1.0 g of sodium hydride and 4.4 g of 2-chlorotetrahydrofuran were added and allowed to react at room temperature for 1 hour. This solution was diluted with diethylether and washed many times with pure water. The organic solvent of the organic phase was evaporated and the residue was subjected to silica gel column chromatography, to obtain 9.3 g of pure 3-(tetrahydrofuranyloxycarbonyl)-1-vinyl-2-pyrrolidinone (hereinafter referred to as “TFVP”). Its chemical structure was determined by IR spectra and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[S:10]([Cl:9])(=[O:12])=[O:11]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=S(=O)(Cl)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.4 %

Procedure:
4-Chlorophenol (4 g, 31.25 mmol) was added in portions to chlorosulfonic acid (10.3 mL, 156 mmol) while cooling in an ice bath. The resulting solution was stirred at 25° C. for 20 hrs. This was then added drop-wise to ice and water resulting in an emulsion. This was extracted with CHCl3, dried (Na2SO4) and concentrated in vacuo. Heptane was added and evaporated and replaced with cyclohexane. The resulting mixture was filtered and concentrated to give the title compound as an oil (2.16 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[C:21]([Br:26])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.CCN(C(C)C)C(C)C>Cl.O1CCOCC1>[Br:26][C:21]1[C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:10]([C@@H:8]([NH:7][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][N:33]4[CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[CH3:9])=[N:11][C:12]=2[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
[(S)-1-(7-Bromo-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (220 mg, 0.66 mmol) was dissolved in hydrochloric acid in dioxane (15 mL, 4M) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo then the residue dissolved in IPA and 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (203 mg, 0.85 mmol) and DIPEA (168 μL, 0.99 mmol) added. The reaction mixture was heated at 90° C. for 16 h then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% methanol in EtOAc) to yield the title compound as a white solid (267 mg, 76%). LCMS (Method C): RT=3.01 min, [M+H]+=537+538.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][C@H:5]([CH:9]([F:11])[F:10])[C@@H:4]([OH:12])[C@@H:3]1[OH:13].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>CN(C=O)C>[F:11][CH:9]([F:10])[C@@H:5]1[C@@H:4]([OH:12])[C@H:3]([OH:13])[C@H:2]2[NH:1][C:14](=[S:15])[O:8][C@H:7]2[CH2:6]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]1O
Solvent: CN(C)C=O
Product: O[C@H]1[C@H](O)[C@@H](C(F)F)C[C@@H]2OC(=S)N[C@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a solution of (1R,2R,3S,4S,6S)-3-amino-6-(difluoromethyl)cyclohexane-1,2,4-triol (300 mg, 1.52 mmol) in DMF (3 mL) at room temperature was added thiocarbonyldiimidazole (298 mg, 1.67 mmol). The mixture was stirred at room temperature for 4 h. Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 5%-8% MeOH in DCM to give the product (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-4,5-dihydroxyhexahydrobenzo[d]oxazole-2(3H)-thione (238 mg, 65%) as a white solid. 1H NMR (400 MHz, MeOD) δ 6.20 (t, J=57.4 Hz, 1H), 4.92-4.96 (m, 1H), 3.71 (t, J=7.1 Hz, 1H), 3.26-3.38 (m, 2H), 2.35 (dt, J=15.3 Hz, 3.0 Hz, 1H), 2.03-2.17 (m, 1H), 1.91-1.99 (m, 1H).