Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[CH:15][C:10]3=[C:9](/[CH:29]=[CH:30]/[C:31]([O:33]CC)=[O:32])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[C:9](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C=C/c1nc(C2CCCCC2)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1nc(C2CCCCC2)n2c1cnc1[nH]ccc12
Temperature: 65 °C
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a solution of (E)-ethyl 3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylate (0.064 g, 0.13 mmol) in 1,4-dioxane (5 mL) was added NaOH (2 N aqueous, 1.30 mL, 2.60 mmol). The reaction mixture was heated to about 65° C. After about 15 h, the reaction mixture was cooled to ambient temperature and the pH of the reaction mixture was adjusted to about pH 1 with concentrated HCl. The mixture was partially concd in vacuo to remove the 1,4-dioxane and the resulting yellow solid was collected by filtration and dried in vacuo to provide (E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylic acid (0.015 g, 37.2%): LC/MS (Table 1, Method a) Rt=1.85 min; MS m/z: 311 (M+H)+.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.FC(F)(F)S(O[C:22]1[C:23]([N+:28]([O-:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1)(=O)=O.O>CC(N(C)C)=O>[F:2][CH:3]1[CH2:8][CH2:7][N:6]([C:22]2[C:23]([N+:28]([O-:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:5][CH2:4]1
Reactant: FC1CCNCC1
Reactant: O=[N+]([O-])c1ncccc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ncccc1N1CCC(F)CC1
Temperature: 110 °C

Procedure:
To a solution of 4-fluoropiperidine hydrochloride (1.54 g, 11 mmol) and triethylamine (4.5 mL, 33 mmol) in dimethylacetamide (30 mL) was added 2-nitropyridin-3-yl trifluoro-methanesulfonate (3.00 g, 11 mmol) and the mixture heated to 110° C. for 1 hour. Water was added and the mixture extracted with ethyl acetate. The organic phase was washed with brine and dried with sodium sulfate. The solvent was evaporated in vacuo and the product used without further purification. The title compound was obtained as a yellow oil (2.22 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([N:16]1[CH2:23][CH:22]2[C:24]([CH3:26])([CH3:25])[CH:18]([CH2:19][NH:20][CH2:21]2)[CH2:17]1)[CH2:13][CH2:14][CH3:15]>ClCCl>[CH2:12]([N:16]1[CH2:17][CH:18]2[C:24]([CH3:25])([CH3:26])[CH:22]([CH2:21][N:20]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:19]2)[CH2:23]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CC2CNCC(C1)C2(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: CCCCN1CC2CN(S(=O)(=O)c3ccc(F)cc3)CC(C1)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A solution of 7.2 g of 4-fluorobenzenesulfonyl chloride in 10 ml of dichloromethane was added dropwise with ice-cooling to a solution of 7.8 g of 7-(n-butyl)-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane in 40 ml of dichloromethane. The ice-cooling was then removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was worked up by adding aqueous sodium bicarbonate solution and extracting twice with dichloromethane. The combined dichloromethane extracts were dried with magnesium sulfate and concentrated. 12.9 g of 7-(n-butyl)-3-[(4-fluorophenyl)sulfonyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane were obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(#N)C.C(OCC)(=O)C>[Br:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21]
Reactant: BrCCCBr
Reactant: O=C(Cc1ccccc1O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1OCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.2 g of potassium carbonate and 40 cm3 of 1,3-dibromopropane are added to a solution of 4.84 g of benzyl [(2-hydroxy)phenyl]acetate in 100 cm3 of acetonitrile. The mixture is stirred at the reflux temperature for 20 hours and then cooled to room temperature before being filtered. The filtrate is concentrated to dryness under reduced pressure and the residue obtained is taken up in 200 cm3 of ethyl acetate. The solution is washed with twice 100 cm3 of water then with 150 cm3 of brine, and is dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (particle size 0.06-0.200 height 30 cm, diameter 5 cm), eluting with a mixture of cyclohexane and ethyl acetate (95:5 by volume) and collecting fractions of 100 cm3. Fractions 18 to 28 are concentrated to dryness under reduced pressure (2.7 kPa). 2.0 g of benzyl [2-(3-bromopropoxy)phenyl]acetate are obtained in the form of an oil.
Reaction SMILES: [CH3:1]S(C)=O.[OH-:5].[Na+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:1]1[O:5][C@@H:13]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: Cc1ccccc1
Reactant: CS(C)=O
Agent: [Na+]
Product: c1ccc([C@@H]2CO2)cc1
Temperature: 0 °C

Procedure:
A solution of 256.7 g. of R-2-phenyl-2-hydroxyethanol in 1000 ml. of toluene containing 50 ml. of pyridine was stirred at 0° C. while a solution of 372.1 g. of p-toluenesulfonyl chloride in 400 ml. of toluene was added dropwise over two hours. The reaction mixture was stirred at 0° C. for forty-eight hours and then filtered to remove the precipitated pyridine hydrochloride. The filtrate was concentrated to dryness by evaporation under reduced pressure to provide the product as an oil. The oil was dissolved in fresh toluene, washed with dilute hydrochloric acid and with water, and dried. Evaporation of the solvent under reduced pressure and crystallization of the product from diethyl ether and hexane afforded 435 g. of R-2-phenyl-2-hydroxy-1-p-toluenesulfonyloxyethane. The product thus formed was dissolved in 1000 ml. of dimethyl sulfoxide containing 418 ml. of 5 N sodium hydroxide. The alkaline solution was stirred at 0° C. for twelve hours, and then was poured into ice water. The product was extracted into 50% diethyl ether-pentane, and the organic layer was separated, washed with water and dried. Removal of the solvent by evaporation afforded, after distillation, 165 g. of R-styrene oxide, B.P. 55°-56° C. 0.6 torr. [α]D -23.7° (chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[N:37]2[CH2:38][CH2:39][NH:40][CH2:41][C:36]2=[CH:35][N:34]=1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11](=[O:13])[N:40]1[CH2:39][CH2:38][N:37]2[C:33]([C:32]([F:43])([F:31])[F:42])=[N:34][CH:35]=[C:36]2[CH2:41]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ncc2n1CCNC2
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(cnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F

Procedure:
Under a nitrogen atmosphere, 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1k (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane under stirring. After stirring at room temperature for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine if (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]carbamic acid tert-butyl ester 1l (20.0 g, yield 88%) as a white solid.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:12])[CH3:11].[NH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH2:19].[H][H]>CO>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH:5]2[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]2)[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: NCCNCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: [H][H]
Solvent: CO
Product: CC1(C)CC(NCCNCCNC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reaction time: 2 h

Procedure:
A Parr shaker bottle containing 20.0 g (0.117 mol) 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one, 6.0 g (0.058 mol) diethylenetriamine, 0.5 g 8% Pt/2% Pd on Carbon and 120 mL methanol is pressurized with hydrogen and shaken for 2 hours. The catalyst is removed by filtration and the solution is concentrated to 40 mL. The product is precipitates as a white solid with the addition of 200 mL of ethyl ether: mp 118-124° C.
Reaction SMILES: [CH:1]1(CN)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14](=[O:26])[C:13]([C:27](O)=[O:28])=[CH:12][C:11]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:1]1([C:12]2[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([CH3:9])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[C:14](=[O:26])[C:13]=2[C:27]([NH2:37])=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: NCC1CCCCC1
Reactant: Cc1c(-c2ccccc2)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(C2CCCCC2)c(C(N)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
(Cyclohexylmethyl)amine in NMP (135 μl, 0.3M, 0.04 mmol) was added to a mixture of 6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydro-pyridine-3-carboxylic acid (12 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol), HOAT (7 mg, 0.04 mmol) and DIEA (13 mg, 0.1 mmol) in NMP (160 μl). The reaction mixture was stirred for 17 h at room temperature. The solvent was removed in vacuo, and the residue was dissolved in acetonitrile/water, 50/50, to a total volume of 1.6 ml, and purified using preparative HPLC to give the title compound (7 mg, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:33]1C=C(S(Cl)(=O)=O)C=C[CH:38]=1>>[CH2:33]([O:28][C:27](=[O:29])[C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])=[CH:31][CH:30]=1)[CH3:38]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1

Procedure:
4-{[1-(3-Fluoro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=439.3 (M−H), was prepared in analogy to example 30, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 4-{[1-(3-fluoro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([OH:13])[C@@H:5]([OH:12])[C@H:6]([OH:11])[C:7](=O)[CH2:8][OH:9].CN(B)C.C(N(CC)CC)C>O>[NH:2]1[C@H:7]([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[CH2:3]1
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Agent: BN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 50 °C

Procedure:
50 g (0.23 mol) of 6-amino-6-desoxy-L-sorbose hydrochloride were dissolved in 500 ml of distilled water, and the solution was added in the course of one hour to a solution of 11.2 g of dimethylaminoborane in 500 ml of distilled water, whilst stirring at a temperature of 50° C. The mixture was stirred for one hour at room temperature and one hour at 50° C., 5 ml of triethylamine were added to it, and it was then poured over a column containing 800 ml of strongly basic ion exchanger ("Lewatit" MP 500 OH- -form). The exchanger was washed with distilled water, and the runnings collected were concentrated to a syrup on a rotary evaporator. The concentrated syrup was crystallised at 50° C., with addition of a large amount of ethanol. The suspension of crystals was cooled and filtered off under suction, and the crystalline product was dried in a vacuum drying cabinet.
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[CH:22][C:20](N)=[N:19][C:17]2=[O:18])[C@H:13]([OH:24])[C@@H:12]1[OH:25])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[OH-:26].[NH4+]>[Rh]>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[CH:22][C:20](=[O:26])[NH:19][C:17]2=[O:18])[C@H:13]([OH:24])[C@@H:12]1[OH:25])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[OH:26][CH:20]1[CH2:22][CH2:23][N:16]([C@@H:14]2[O:15][C@H:11]([CH2:10][OH:9])[C@@H:12]([OH:25])[C@H:13]2[OH:24])[C:17](=[O:18])[NH:19]1
Reactant: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: [OH-]
Agent: [Rh]
Agent: [NH4+]
Product: O=C1NC(O)CCN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1

Procedure:
In the manner given in Example 2D, cytidine 5'-diphosphate was hydrogenated in dilute ammonium hydroxide in the presence of a rhodium on alumina catalyst, and the mixture separated with a Craig extractor to give 4-hydroxy-1-β-D-ribofuranosyl-tetrahydro-2(1H)-pyrimidinone uridine 5'-diphosphate and 1-β-D-ribofuranosyl-tetrahydro-2(1H)-pyrimidinone 5'-diphosphate.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH:34]CC(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][OH:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NNC(=O)CO
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Product: Cc1cc(C2CCC2)c(-c2nnc(CO)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 152 but using 2-hydroxyacetohydrazide in place of acetohydrazide. m/z (ES+) 456 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10](Cl)=[N:9][CH:8]=[N:7]2.C(OC([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)=O)(C)(C)C.C([O-])(O)=O.[Na+].[Cl:32][C:33]1[CH:34]=[C:35]([NH2:48])[CH:36]=[CH:37][C:38]=1[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1>C(#N)C>[Cl:32][C:33]1[CH:34]=[C:35]([NH:48][C:10]2[C:11]3=[C:3]([CH2:2][O:26][CH:23]4[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]4)[CH:4]=[CH:5][N:6]3[N:7]=[CH:8][N:9]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnn2ccc(CBr)c12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Fc1cccc(COc2ccc(Nc3ncnn4ccc(COC5CCNCC5)c34)cc2Cl)c1
Reaction time: 8 h
Yield: 48.1 %

Procedure:
A solution of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.408 mmole), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.56 gm, 7.76 mmole) and NaHCO3 (131 mg, 1.56 mmol) in dry acetonitrile (5 mL) was stirred at RT for 3 days. 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine 3A (92 mg, 0.367 mmole) and additional NaHCO3 (131 mg, 1.56 mmol) were added and the reaction was left stirring overnight. The solvent was removed and the residue was partitioned between DCM and water. The organic phase was separated, dried (Na2SO4), and the solvent removed. The residue was treated with a mixture of TFA:DCM (1:1) at 0° C. for 80 min and the solvents were removed. The residue was taken up in DCM, washed with a sat. aq. NaHCO3 solution and then dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate eluted with DCM containing 5% of a 2 M solution of NH3 in MeOH) afforded the titled product as an oil (85 mg, 43%). Analytical HPLC retention time=1.60 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=482.
Reaction SMILES: [S:1](=[O:3])=[O:2].N[C:5]1[CH:6]=[C:7]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[NH:12]2)[CH:8]=[CH:9][CH:10]=1.N([O-])=O.[Na+].[ClH:31]>C(O)(=O)C.O>[Cl:31][S:1]([C:5]1[CH:6]=[C:7]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cuprous chloride (90 mg, 0.91 mmol) in acetic acid (60 mL) was bubbled with sulfur dioxide gas for 6 h at room temperature. A mixture of methyl 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (992 mg, 3.20 mmol) in conc. hydrochloric acid (30 mL) and acetic acid (10 mL) was stirred for 1 hour. After cooling to −10° C., a solution of sodium nitrite (334 mg, 4.84 mmol) in water (7 mL) was added dropwise below −10° C. The resulting mixture was stirred for 1 h at −10° C. The prepared sulfur dioxide-salt solution was added to the solution above at −10° C. After addition, the mixture was stirred for 24 h at room temperature. The reaction mixture was quenched onto 100 g of crushed ice. The mixture was extracted with dichloromethane (40 mL, four times). The combined organic layers were washed with water (40 mL, twice), saturated aqueous Sodium bicarbonate solution (30 mL, twice), and saturated brine (40 mL) and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed by filtration, and the organic solvent was evaporated under reduced pressure to afford 1.0 g of methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate. MS (ESI+APCI) M+1=394.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH:22]([NH2:24])[CH3:23].CCN(C(C)C)C(C)C>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH:22]([CH3:23])[CH2:21][O:20][CH3:19])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COCC(C)N
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.1 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of 2-methoxy-1-methyl-ethylamine (0.12 g, 1.32 mmol) and Hunig's base (0.037 g, 0.29 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature and extracted with EtOAc/H2O. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to yield 0.20 g (87%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 356.2 [(M+H)+, 86].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22](O)[CH3:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1.C1(C)C=CC=CC=1.[N:32]12CCCN=C1CCCCC2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]([NH2:32])[CH3:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: CC(O)c1ccc2c(c1)ncn2-c1cccc(-c2ncc(Cl)s2)c1
Reactant: C1CCC2=NCCCN2CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(N)c1ccc2c(c1)ncn2-c1cccc(-c2ncc(Cl)s2)c1
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 75.5 %

Procedure:
A stirred suspension of 1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzoimidazol-5-yl}-ethanol (1.0 g, 2.80 mmol) in a mixture anhydrous toluene (60 ml) and THF (10 ml) was cooled to 10° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 ml, 3.36 mmol) and di-phenylphosphoryl azide (0.95 g, 3.36 mmol) were added, successively. Stirring was continued for 45 min at 10° C., whereafter the temperature was raised and the mixture was stirred at reflux for two days. The cooled mixture was concentrated in vacuo and the concentrate was partitioned between ethyl acetate and saturated, aqueous sodium carbonate. The organic extract was dried over magnesium sulphate, concentrated under reduced pressure and eluted through silica gel with a mixture of dichloro-methane, methanol and aqueous ammonia (9:1:0.1 v/v/v) to afford the desired product (0.75 g, 70%). LC-ESI-HRMS of [M+H]+ shows 355.079 Da. Calc. 355.07842 Da. dev. 1.6 ppm.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C@H:4]1[CH2:6][O:5]1.[N-:9]=[N+:10]=[N-:11].[Na+].[NH4+].[Cl-]>CCO.O>[N:9]([CH2:6][C@@H:4]([OH:5])[CH2:3][C:2]([F:8])([F:7])[F:1])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NC[C@@H](O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
To a solution of (S)-2-(2,2,2-trifluoroethyl)oxirane (2.00 g, 16.0 mmol) in a mixture of EtOH (16 mL) and H2O (4 mL) were added NaN3 (2.06 g, 32.0 mmol) and NH4Cl (1.70 g, 32.0 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with H2O (50 mL), extracted with Et2O (2×75 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give (S)-1-azido-4,4,4-trifluorobutan-2-ol as an oil (2.26 g, 83% yield). NMR: 400 MHz 1H (CDCl3) 4.17 ppm, 1H, ddd, J=6.81, 3.74, 3.52 Hz; 3.48 ppm, 1H, m; 3.37 ppm, 1H, m; 2.35 ppm, 2H, m.
Reaction SMILES: C(OC1C=CC(N)=CC=1)C1C=CC=CC=1.N1C=CC=C1C(O)=O.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([C:41]2[CH:46]=[CH:45][CH:44]=C[N:42]=2)=[O:40])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]([C:41]2[NH:42][CH:44]=[CH:45][CH:46]=2)=[O:40])=[CH:36][CH:37]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Agent: Nc1ccc(OCc2ccccc2)cc1
Agent: O=C(O)c1ccc[nH]1
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc[nH]1

Procedure:
This compound was prepared from 4-benzyloxyaniline (4.0 g, 17 mmol) and pyrrole-2-carboxylic acid (1.98 g, 17.8 mmol), using the same method used to prepare pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide. The product was purified by flash chromatography, on silica gel, using 5% methanol in DCM as the eluant, to give the product as a colorless solid, 2.6 g (50%). MS m/z 293 (MH+). 1H NMR (DMSO-d6) δ 5.04 (s, 2H), 6.13 (m, 1H), 6.95-7.05 (m, 4H), 7.28-7.45 (m, 5H), 7.65 (d, 2H), 9.7 (s, 1H) and 11.65 (s, 1H).