Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)=O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].O.[ClH:37]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[Cl:37][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: Cl
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(CCl)o1
Reaction time: 2.5 h

Procedure:
To a three-necked flask equipped with a condenser and a stirrer were added 5 g (0.028 mole) of a commercially available D-(-)-fructose and two kinds of surface active agent, i.e., 89.6 mg (0.00028 mole) of cetyltrimethylammonium chloride and 97.6 mg (0.00028 mole) of sodium laurylbenzenesulfonate. Then, 5 ml of water and 30 ml of toluene were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride (about 15 g) was passed through the mixture at room temperature for about 40 minutes with thorough stirring. After stirring was continued at room temperature for a further 2.5 hours, the upper toluene layer was separated from the lower aqueous layer. Thirty milli-liters of toluene and the above two surface active agents in the same amounts as above were then freshly added to the aqueous layer. After the mixture was stirred at room temperature for 2.5 hours, the upper toluene layer was again separated. This toluene extraction operation was repeated three times in total. All the toluene layers were combined and filtered through Celite. The filtrate was neutralized with an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. Thus, about 3.10 g (theoretical yield 4.01 g) of 5-chloromethylfurfural was obtained as a crude liquor of pale brown color.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:6]=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: C=CCOC(=O)c1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(CBr)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of allyl 6-(hydroxymethyl)pyridine-2-carboxylate (1.0 g, 5.17 mmol) in 20 mL of CH2Cl2 is cooled to 0° C. under argon and 3.43 g (10.3 mmol) of CBr4 is added. Then, 1.5 g (5.69 mmol) of triphenyl phosphine is added in several portions over 20 min. The reaction is allowed to stir at 0° C. for 3 h and is then concentrated in vacuo and applied to a short silica gel column. Elution with 1:1 EtOAc-hexane yields allyl 6-(bromomethyl)pyridine-2-carboxylate as an oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:40])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:24](=[S:25])[N:23]([C:26]3[CH:27]=[N:28][C:29]([C:36]#[N:37])=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=3)[C:22](=[O:38])[C:18]32[CH2:21][CH2:20][CH2:19]3)=[CH:13][C:12]=1[F:39])(=O)=O.Cl.[F:42][C:43]1([F:48])[CH2:47][CH2:46][NH:45][CH2:44]1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[C:36]([C:29]1[N:28]=[CH:27][C:26]([N:23]2[C:22](=[O:38])[C:18]3([CH2:21][CH2:20][CH2:19]3)[N:17]([C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:45]4[CH2:46][CH2:47][C:43]([F:48])([F:42])[CH2:44]4)=[O:40])=[C:12]([F:39])[CH:13]=3)[C:24]2=[S:25])=[CH:31][C:30]=1[C:32]([F:33])([F:35])[F:34])#[N:37]
Reactant: CS(=O)(=O)OCCCNC(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCCCN4CCC(F)(F)C4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 70 °C
Yield: 9.2 %

Procedure:
A mixture of 3-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)propyl methanesulfonate (45 mg, 0.075 mmol), 3,3-difluoropyrrolidine hydrochloride (54 mg, 0.37 mmol), and triethylamine (0.14 mL, 1.05 mmol) in THF (2 mL) was heated to 70° C. overnight. Brine and EtOAc were added to a cooled reaction mixture and the aqueous layer was extracted with EtOAc (2×), the organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue obtained was purified by reverse phase HPLC (acetonitrile/water:TFA) to obtain 4.2 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-2-fluorobenzamide. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.68 (d, 1H), 8.51 (t, 1H), 7.72 (t, 1H), 7.39 (dd, 1H), 7.30 (dd, 1H), 3.25 (m, 4H), 2.80 (t, 2H), 2.64-2.58 (m, 4H), 2.44-2.40 (m, 2H), 2.16 (m, 2H), 1.91 (m, 1H), 1.64-1.45 (m, 3H). LCMS [M+1]+ 611.1.
Reaction SMILES: [C:1]1([C:7]([CH3:11])=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([S:18]([C:21]#[N:22])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(OCCCC)(OCCCC)OCCCC>>[C:12]1([S:18]([C:21]2[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=[CH:9][N:22]=2)(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: CC(=CC=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Product: O=S(=O)(c1ccccc1)c1cc(-c2ccccc2)ccn1
Temperature: 112 °C
Yield: 68.7 %

Procedure:
First, 0.93 g (6.36 mmol) of 3-phenyl-2-butenal and 0.99 g (5.91 mmol) of benzenesulfonyl cyanide were introduced to a 3-necked flask (25 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver, and a condenser tube. Toluene (5 ml) as the solvent and butanol (0.5 ml) were added, and 0.14 g (0.59 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 2 hours while agitating at an internal temperature of 112° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=¼) to give 1.20 g of 2-benzenesulfonyl-4-phenylpyridine with the following properties as colorless crystals (purity of 99%, yield of 71% based on benzenesulfonyl cyanide).
Reaction SMILES: N[C:2]1[C:7]2[O:8][CH2:9][CH2:10][C:11]3([S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.F[B-](F)(F)F.[H+].N([O-])=[O:26].[Na+]>O>[F:18][C:4]1[CH:3]=[C:2]([OH:26])[C:7]2[O:8][CH2:9][CH2:10][C:11]3([S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[C:6]=2[CH:5]=1
Reactant: Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: O=C1NC(=O)C2(CCOc3c(O)cc(F)cc32)S1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
268 mg of (±)-8-amino-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione were introduced into 3 ml of 50% tetrafluoroboric acid and the mixture was treated dropwise in an ice-bath with a solution of 76 mg of sodium nitrite in 0.3 ml of water. The mixture was subsequently stirred at room temperature for 90 minutes and then excess nitrite was destroyed by the addition of some urea. The solution of the diazonium salt was introduced in one portion into a solution of 12.08 g of copper (II) nitrate in 25 ml of water with vigorous stirring. After the addition of a small spatula tip of copper (I) oxide, vigorous gas evolution occurred. The mixture was stirred at room temperature until the foaming had finished (about 90 minutes). The product was thereupon extracted with three portions of ether, the organic phases were washed four times with water and dried with sodium sulfate. The residue remaining after removal of the solvent by concentration was separated by chromatography on preparative thick-layer plates and the (±)-6-fluoro-8-hydroxy-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione was isolated as a non-crystallizable, solid material.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][CH2:3][C:2]([F:16])([F:15])[F:1])=[CH:7][CH:8]=1)[CH3:13])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCCC(F)(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCCC(F)(F)F)nc1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (0.95 g, a white solid) from 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (0.82 g, 3.51 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[CH:4]([NH:9][C:10](=[O:57])[CH2:11][N:12]1[C:16]([CH3:27])([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:15](=[O:28])[N:14]([CH2:29][CH2:30][CH2:31][C:32]2[N:33]=[CH:34][N:35](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:36]=2)[C:13]1=[O:56])[CH2:5][CH2:6][S:7][CH3:8].C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:58])[CH:4]([NH:9][C:10](=[O:57])[CH2:11][N:12]1[C:16]([CH3:27])([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:15](=[O:28])[N:14]([CH2:29][CH2:30][CH2:31][C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)[C:13]1=[O:56])[CH2:5][CH2:6][S:7][CH3:8]
Reactant: COC(=O)C(CCSC)NC(=O)CN1C(=O)N(CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)C1(C)c1cccc2ccccc12
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CCSC)NC(=O)CN1C(=O)N(CCCc2c[nH]cn2)C(=O)C1(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
0.11 g(0.13 mmol) of 2-(2-{3-[3-(1-triphenylmethyl-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester prepared in Example 1-3) and 0.053 ml(0.26 mmol) of triisopropylsilane were dissolved in 5 ml of methylene chloride. Then, 5 ml of trifluoroacetic acid was added thereto and the resulting solution was stirred for one hour at room temperature. The organic solvent was removed under reduced pressure and saturated potassium carbonate[K2CO3] solution was added. The solution was extracted with 10 of ethyl acetate and the solvent was removed under reduced pressure. The residue was subjected to chromatography using a solvent mixture of methanol-methylene chloride(5:95) as the eluent to obtain 0.068 g(Yield: 95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[CH:17]=[CH:16][N:15](C(OCC3C=CC=CC=3)=O)[CH2:14][C:13]2=[O:28])[CH2:7][CH2:6]1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:28])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](CN2C=CN(C(=O)OCc3ccccc3)CC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CN2CCNCC2=O)CC1

Procedure:
A solution of 1-(trans-4-methoxycarbonylcyclohexylmethyl)-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (2.0 g) and 10% palladium on carbon (400 mg) in methanol (80 ml) was stirred at room temperature for 15 hours, under hydrogen atmosphere, and the catalyst was filtered off. The reaction solution was concentrated to give colorless oil of 1-(trans-4-methoxycarbonylcyclohexylmethyl)-2-piperazinone. To the obtained 1-(trans-4-methoxycarbonylcyclohexylmethyl)-2-piperazinone were added ethyl acetate (20 ml) and sodium bicarbonate solution (20 ml), and then was added 6-chloro-2-naphthanlenesulfonyl chloride (1.5 g), and the mixture was stirred at room temperature for 5 hours. The separated organic layer was washed with water and brine, dried and concentrated, and the residue was crystallized from ethyl acetate to give colorless crystals of 4-(6-chloro-2-naphthanlenesulfonyl)-1-(trans-4-methoxycarbonylcyclohexylmethyl)-2-piperazinone (1.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11](NN)=[O:12])[NH:6]2.CC1C=CC(S(Cl)(=O)=O)=CC=1.Cl>N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]=[O:12])[NH:6]2
Reactant: Cc1cccc2[nH]c(C(=O)NN)cc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc2[nH]c(C=O)cc12
Temperature: 0 °C

Procedure:
23.0 g 4-methylindole-2-carboxylic acid hydrazide were added in small portions, while stirring and during ice cooling, to the solution of 23.0 g p-toluene sulfochloride in 300 ml pyridine. Then it was stirred for another hour in the ice bath and for another hour at room temperature, poured onto a mixture of 350 ml concentrated hydrochloric acid and ice, the precipitated 4-methylindole-2-carboxylic acid-(N'-tosyl-hydrazide) filtered off with suction and thoroughly washed with well diluted hydrochloric acid, then with water.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@@:9]([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)([O:23][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1cccc(C(F)(F)F)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-Trifluoromethyl-benzoic acid to yield (3aR,4S,7aR)-4-m-tolylethynyl-4-(3-trifluoromethyl-benzoyloxy)-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=8.705 min; LC-MS Method III
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([N:20]([O:21][CH3:22])[CH3:19])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-bromo-2-fluorobenzoic acid (29 g, 132 mmol) in anhydrous DCM (500 mL) was added oxalyl chloride (16.8 mL, 199 mmol) and 5 drops of DMF. The suspension was stirred at room temperature for 2 hours. The solvent and excess oxalyl chloride were removed by rotary evaporation, and the residue was dissolved in anhydrous DCM (500 mL). With vigorous stirring, N,O-dimethylhydroxylamine hydrochloride (16.8 g, 172.3 mmol) was added in one portion, followed by triethylamine (80 mL, 574 mmol). The thick suspension was stirred for 1 hour at room temperature and then filtered. The organic layer was washed sequentially with 1M HCl, 1M NaOH, and water, dried over Na2SO4, and concentrated to afford the product. 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J=5.7, 2.5 Hz, 1H), 7.50 (ddd, J=8.7, 4.6, 2.5 Hz, 1H), 7.00 (t, J=8.8 Hz, 1H), 3.56 (s, 3H), 3.34 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][C@@H:16]([CH3:18])[NH:15][C@@H:14]([CH3:19])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(Cl)Cl>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@@H:16]([CH3:18])[N:15]([C:1](=[O:3])[CH3:2])[C@@H:14]([CH3:19])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1[C@H](C)CN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Acetyl chloride (0.216 ml, 3.04 mmol) was added to a stirred solution of (3S,5R)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) and TEA (0.49 ml, 3.51 mmol) in DCM (20 ml). The mixture was stirred at room temperature overnight, then the solvent was evaporated and the residue was partitioned between Et2O and 5% citric acid. The organic phase was dried over Na2SO4 and evaporated in vacuo to give 545 mg of (3S,5R)-4-acetyl-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]([O:17][CH3:18])[O:15][CH3:16].C[O-].[Na+]>CO>[CH3:18][O:17][CH:14]([O:15][CH3:16])[CH:13]([S:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COC(OC)C(Br)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1SC(c1ccccc1)C(OC)OC
Yield: 70 %

Procedure:
In each case 10 ml of methyl 2-mercaptobenzoate and 2-bromo-1,1-dimethoxy-2-phenylethane are refluxed overnight in 30 ml of methanol, with addition of 10 ml of NaOMe. After working up and purification by chromatography, 70% of viscous oil is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22][N:21]=3)=[N:15][CH:16]=[C:17]([F:18])[C:12]2=[N:11]1)[CH:5]=[O:6].[BH4-].[Na+].Cl>C(O)C.C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22][N:21]=3)=[N:15][CH:16]=[C:17]([F:18])[C:12]2=[N:11]1
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4Cl)cc23)ncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(CO)cc4Cl)cc23)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of 3,5-dichloro-4-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzaldehyde (125 mg, 0.3 mmol) in ethanol (IMS grade, 5 mL) and THF (2 mL) was added sodium borohydride (14 mg, 0.36 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-1% methanol in ethyl acetate) to yield a solid, to which was added HCl (1.25 N in propan-2-ol, 10 mL) and the mixture was stirred at room temperature for 1 hour. The solid obtained was collected by filtration and dried to afford the title compound as an off-white solid (62 mg, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.35 (br s, 1H), 8.97 (s, 1H), 8.36 (br s, 1H), 8.10 (d, J=3.5 Hz, 1H), 7.75 (s, 2H), 4.68 (s, 2H), 2.57 (s, 3H). LCMS (Method B): RT=2.89 min, m/z: 419 [M+H+].
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:34]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:35]3[N:34]=[N:33][CH:38]=[CH:37][CH:36]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2cccnn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.017, 0.095 mmol, 1 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.029 g (57%). 1H NMR (400 MHz, CD3OD): δ 9.14 (d, J=3.6 Hz, 1H), 7.97-7.85 (m, 6H), 7.56 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.89-1.86 (m, 2H), 1.62-1.59 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ−77.63 (TFA), −112.22, −112.77 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.O.COC1C=C(OC)C=CC=1C[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][N:21]([C@H:24]3[C@H:31]4[C@H:27]([O:28]C(C)(C)[O:30]4)[C@@H:26]([CH2:34][N:35]([CH:56]([CH3:58])[CH3:57])[CH:36]4[CH2:39][CH:38]([CH2:40][CH2:41][C:42]5[NH:46][C:45]6[CH:47]=[CH:48][C:49]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:50][C:44]=6[N:43]=5)[CH2:37]4)[CH2:25]3)[C:17]=2[N:18]=[CH:19][N:20]=1.C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:14][C:15]1[C:16]2[CH:23]=[CH:22][N:21]([C@@H:24]3[CH2:25][C@H:26]([CH2:34][N:35]([CH:56]([CH3:57])[CH3:58])[CH:36]4[CH2:37][CH:38]([CH2:40][CH2:41][C:42]5[NH:46][C:45]6[CH:47]=[CH:48][C:49]([O:51][C:52]([F:53])([F:55])[F:54])=[CH:50][C:44]=6[N:43]=5)[CH2:39]4)[C@@H:27]([OH:28])[C@H:31]3[OH:30])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(OC(F)(F)F)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CC(C)N(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(OC(F)(F)F)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Trifluoroacetic Acid (10 mL, 100 mmol) added to a mixture of Water (1 mL, 60 mmol) and N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-6-((isopropyl(3-(2-(5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.91 g, 1.2 mmol) at RT. The reaction was stirred overnight at RT then quenched by the addition of Triethylsilane (0.37 mL, 2.3 mmol). The volatiles were removed in vacuo and resulting residue was taken up in MeOH (15 mls). 500 mgs of K2CO3 and 8 drops H2O were added and reaction stirred at RT for 1 hour. Mixture was filtered and filter cake washed with 10 mls MeOH. The filtrate was concentrated and the resulting residue purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to yield the desired product (0.232 g) as an off white foam. MS (ESI+) for C29H36F3N7O3 m/z 588.2 [M+H]+; MS (ESI−) for C29H36F3N7O3 m/z 586.2 [M−H]−; HPLC purity >90% (ret. time, 2.570 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.082 & 8.079 (s, 1H, overlapping peaks due to cis and trans isomers), 7.554-7.524 (m, 1H), 7.414 (s, 1H), 7.225-7.209 (m, 1H), 7.155-7.127 (m, 1H), 6.618-6.609 (m, 1H), 4.363-4.323 (m, 1H), 3.976-3.932 (m, 1H), 3.606-3.524 (m, 0.5H (methine from trans isomer)), 3.156-3.110 (m, 0.5H (methine from cis isomer), 3.089-3.006 (m, 1H), 2.731-2.679 (m, 1H), 2.544-2.360 (m, 2H), 2.256-2.239 (m, 3H), 2.093-2.061 (m, 2H), 1.987-1.861 (m, 3H), 1.648-1.568 (m, 2H), 1.072-1.006 (m, 6H).