Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([O:18]C)=[O:17])=[CH:14][C:13]([S:20]([CH3:23])(=[O:22])=[O:21])=[N:12]2)=[CH:7][CH:6]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([S:20]([CH3:23])(=[O:22])=[O:21])=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(S(C)(=O)=O)nn1-c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nc(S(C)(=O)=O)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
A solution of lithium hydroxide (1.3 mL, 1.0 M, 1.3 mmol) was added to a suspension of methyl 1-(4-methoxyphenyl)-3-methylsulfonyl-pyrazole-5-carboxylate (272 mg, 0.88 mmol) in MeOH (10 mL) and stirred at room temperature 17 hours. The resulting mixture was concentrated and partitioned between EtOAc and H2O. The organic extracted was removed, and the aqueous extract was acidified with 1M HCl and extracted twice with EtOAc. The organic extracts from this extraction were combined, dried over Na2SO4, filtered, and evaporated to yield product (266 mg). 1H NMR (CDCl3+few drops MeOD): δ7.45 (s, 1H), 7.38 (d, 2H, J=9.2), 6.96 (d, 2H, J=9.2), 3.86 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:22][C:11]3=[N:12][C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([I:16])[CH:15]=[C:10]3[C:9]=2[C:23]([NH:25][CH3:26])=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38].CN(C=O)C>O>[CH3:26][NH:25][C:23]([C:9]1[C:10]2[C:11](=[N:12][C:13]([N:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:38][CH2:37][CH2:36][CH:35]=[CH2:34])=[C:14]([I:16])[CH:15]=2)[O:22][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:24]
Reactant: C=CCCCBr
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(methylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (440 mg), Cs2CO3 (322 mg, 1.1 eq.), 5-bromopent-1-ene (402 mg, 3 eq.) and dry DMF (4.5 ml) was stirred in a microwave reactor at 150° C. for 15 min and cooled to rt. Water was added and the mixture was extracted with methylene chloride. The organic layer was washed with 2× water. Silica gel flash chromatography using 0-11% ether-methylene chloride yielded the title compound (250 mg, 55%). MS (ESI) m/z 558.1 (M+1). Retention time=1.33 min (Method A).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:12][C:13]1[S:17][C:16]2=[N:18][C:19]([C:21](O)=[O:22])=[CH:20][N:15]2[CH:14]=1>>[Br:12][C:13]1[S:17][C:16]2=[N:18][C:19]([C:21]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[O:22])=[CH:20][N:15]2[CH:14]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: CC(C)c1ccc(CN)cc1
Product: CC(C)c1ccc(CNC(=O)c2cn3cc(Br)sc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (4-isopropylphenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:9]=[N-:10].[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([N:8]=[N+:9]=[N-:10])=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cccs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cccs1)N=[N+]=[N-]
Temperature: 10 °C
Yield: 55.5 %

Procedure:
A solution of thiophene-2-carbaldehyde (650 mg, 5.8 mmol) and ethyl azidoacetate (6.89 grams, 53.4 mmol) in dry toluene (40 ml) was added to a cold (−5° C.) solution of sodium ethoxide (about 53 mmol) in ethanol (60 ml) during a time period of one hour, under nitrogen atmosphere. Stirring was continued for another hour while maintaining the temperature under 10° C. The reaction mixture was then cooled to 0° C. and acidified with HCl 0.1 M. After separation of the phases, the aqueous phase was extracted with ether (3×30 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 718 mg of pure 2-azido-3-thiophen-2-yl-acrylic acid ethyl ester (55% yield).
Reaction SMILES: [CH:1]1([N:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]([CH3:18])[CH2:9]2)[C:5](=[O:7])[CH3:6])[CH2:3][CH2:2]1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([N:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:20]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:27])[CH:10]([CH3:18])[CH2:9]2)[C:5](=[O:7])[CH3:6])[CH2:2][CH2:3]1
Reactant: CC(=O)N(C1CC1)C1CC(C)Nc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C1CC1)C1CC(C)N(C(=O)c2cccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To the solution of N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-acetamide (82 mg, 0.34 mmol) in DCM (5 mL) was added nicotinoyl chloride hydrochloride (71 mg, 0.40 mmol), followed by DIPEA (104 mg, 0.80 mmol). The reaction mixture was stirred at r.t. for overnight. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 mL). The reaction mixture was washed with sat. sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford slightly yellow solid product (81 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(F)cc1Cl
Yield: 62 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2-chloro-4-fluorobenzenesulfonyl chloride (12.6 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 62% yield (10.9 mg). MS (ESI+) calcd mass for C13H9ClFN5O2S 353.014951, found 353.015041.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:31][CH2:30][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1.N1CCC[C@@H:39]1CO>>[CH:5]1([N:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=3)[NH:19][CH:18]=[C:17]4[CH:26]3[CH2:27][CH2:28][N:29]([S:32]([CH:35]([CH3:36])[CH3:37])(=[O:34])=[O:33])[CH2:30][CH2:31]3)[CH:10]=2)[CH3:39])[CH2:2][CH2:3][CH2:7][CH2:6]1
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C5CCCC5)c4)cc23)CC1
Yield: 54.3 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting N-methylcyclopentanamine (90.13 mg, 1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 10 mg of the title compound (54.3%)
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[O:9][C:8]([CH2:11][O:12][CH2:13][O:14][CH3:15])([CH3:10])[CH2:7][C:6]=2[C:16]=1[CH3:17].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:15][O:14][CH2:13][O:12][CH2:11][C:8]1([CH3:10])[CH2:7][C:6]2[C:16]([CH3:17])=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]=2[O:9]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COCOCC1(C)Cc2c(C)c(Br)c(C)c(C)c2O1
Product: COCOCC1(C)Cc2c(C)c(N3CCN(c4ccc(OC)cc4)CC3)c(C)c(C)c2O1
Yield: 47.5 %

Procedure:
By using 5-bromo-2-[(methoxymethoxy)methyl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (1.62 g, 4.92 mmol) synthesized in Reference Example 163 and 1-(4-methoxyphenyl)piperazine (1.89 g, 9.84 mmol), the reaction was carried out in the same manner as Example 1 to synthesize 1.03 g of the title compound (yield 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C:10]([CH3:12])=[CH2:11]>C(O)C>[CH2:15]([O:14][C:9]([CH:10]([CH3:12])[CH2:11][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13])[CH3:16]
Reactant: C=C(C)C(=O)OCC
Reactant: NCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)CNCc1ccccc1
Yield: 60.2 %

Procedure:
To a solution of benzylamine (75 g) in ethanol (150 ml) was added ethyl methacrylate (240 g) and refluxed for 23 hours. The reaction mixture was evaporated and the resulting residue was distilled under reduced pressure to give N-(2-ethoxycarbonylpropyl)benzylamine (93.3 g) as colorless liquid, bp 122° C./4 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:23]=[CH:22][C:12]([CH2:13]P(=O)(OCC)OCC)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[OH:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.CCCCCC.CCOC(C)=O>C1COCC1>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12](/[CH:13]=[CH:37]/[C:36]4[CH:39]=[CH:40][C:33]([OH:32])=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(C)cc3s2)cc1)OCC
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc(O)cc4)cc3)sc2c1
Yield: 66.8 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.10 g, 0.266 mmol) in dry THF (10 ml), potassium t-butoxide (0.063 g, 0.559 mmol) and 4-hydroxybenzaldehyde (0.033 g, 0.266 mmol) in dry THF (5 ml) to give the title compound (0.061 g, 67%) as a pale orange solid after work-up and flash chromatography (2:1 Hexane/EtOAc).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH3:22]>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:21][CH3:22]
Reactant: CCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O

Procedure:
Rats receiving intragastric pretreatment with PL solution only had 3 hours after ethanol macroscopic hemorrhagic lesions involving 35.8±2% of glandular mucosal area. Treatment with oleic acid did not change significantly occurrence of mucosal hemorrhagic lesions--29.1±3%. Rats receiving pretreatment with 120 mM and 240 mM LLC had significantly decreased macroscopic hemorrhagic lesions--6.5±1% and 1.3±0.5% respectively (p<0.01) 3 hours after ethanol. Macroscopic protection rat gastric mucosa against ethanol was similar to that afforded by arachidonic acid except for the presence of marked edema in the forestomach (containing squamous, paraepidermoidal epithelium) 3 hours after ethanol in group pretreated with linoleic acid (C).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(C)o3)C[C@H]2OC)nc1Cl
Yield: 98.5 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (106d) (0.32 g, 0.69 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (2 mL) and THF (5 mL), to obtain 0.28 g of the title compound as a colorless solid (99%).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>ClCCl.O>[CH2:23]([O:22][C:20]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])=[O:21])[CH:24]=[CH2:25]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a suspension of (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (17.0 g: 100 mmole) in dichloromethane (200 ml), triethylamine (29.2 ml: 210 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 5 minutes at room temperature, mixed dropwise with a solution of allyl chloroformate (11.2 ml: 100 mmole) in dichloromethane (20 ml), stirred for 1 hour at room temperature, and diluted with water (250 ml). The organic layer is taken, successively washed with water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (21.82 g) as oil. To a solution of this product in dichloromethane (100 ml), triethylamine (16.7 ml: 120 mmole) and methanesulfonylchloride (9.2 ml: 120 mmole) are added in a nitrogen atmosphere under ice cooling, and the mixture is stirred for 10 minutes. The reaction mixture is successively washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (tolueneethyl acetate) to give (2S, 4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (27.62 g) as oil. Yield: 90%. NMR δ(CDCl3) ppm: 2.2 to 2.4(m, 1H), 2.2 to 2.5(m, 1H), 2.5 to 2.8(m, 2H), 3.06(s, 3H), 3.74 & 3.77(2×s, 3H), 3.8 to 4.0(m, 2H), 4.4 to 4.7(m, 3H), 5.2 to 5.4(m, 3H), 5.8 to 6.0(m, 1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33].N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[O:8][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33]
Reactant: O=Cc1cccc(O)c1
Reactant: OC1CC2C=CC1C2
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cccc(OC2CC3C=CC2C3)c1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
3 g of bicyclo[2.2.1)hept-5-en-2-ol (27.2 mmol) and then 7.86 g of triphenylphosphine (30 mmol) are introduced at 0° C. into a solution of 3.66 g of 3-hydroxybenzaldehyde (30 mmol) in tetrahydrofuran (40 ml), and 13.6 ml of ethyl azodicarboxylate (40% in toluene, 30 mmol) are then added dropwise. The mixture is stirred at 75° C. for 48 hours, the solvent is then evaporated off, the residue is taken up in dichloromethane and the mixture is washed with normal aqueous sodium hydroxide solution, water and then saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulfate, filtered and concentrated. The title product is isolated by chromatography on a column of silica (eluent: 88/12 cyclohexane/ethyl acetate). 0.6 g of a colorless oil is obtained:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:5]2[N:10]=[N:9][N:8](CC3C=CC(OC)=CC=3)[C:6]=2[N:7]=1.[CH:33]([O:36][C:37]1[CH:43]=[C:42]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[C:41]([CH3:50])=[CH:40][C:38]=1[NH2:39])([CH3:35])[CH3:34]>Cl.O1CCOCC1>[CH:33]([O:36][C:37]1[CH:43]=[C:42]([CH:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]2)[C:41]([CH3:50])=[CH:40][C:38]=1[NH:39][C:2]1[N:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])[C:5]2[N:10]=[N:9][NH:8][C:6]=2[N:7]=1)([CH3:35])[CH3:34]
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Reactant: COc1ccc(Cn2nnc3c(Nc4ccccc4S(=O)(=O)C(C)C)nc(Cl)nc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3nn[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 110 °C

Procedure:
A solution of 5-chloro-N-(2-(isopropylsulfonyl)phenyl)-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (10 mg) and 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (7 mg) in 2 M HCl/dioxane (2 mL) was sealed in a pressure tube and heated at 110° C. for 2 days. It was cooled to room temperature and solvent was removed under reduced pressure. The remaining residue was dissolved in trifluoroacetic acid (2 mL) and heated to 80° C. for 2 h. Trifluoroacetic acid was removed and the remaining product was purified by preparative LC-MS to afford desired product. 1H NMR (400 MHz, MeOD-d4) δ 8.67 (d, 1H), 7.98 (m, 2H), 7.74 (t, 1H), 7.43 (t, 1H), 6.82 (s, 1H), 4.61 (m, 1H), 3.57 (m, 2H), 3.38 (m, 1H), 3.18-3.24 (m, 2), 2.26 (s, 3H), 2.03 (m, 2H), 1.82-1.93 (m, 2H), 1.41 (d, 6H), 1.31 (d, 6H) ppm; ESMS calculated for C28H36N8O3S (m/z): 564.2 (M+H+), found: 565.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]1[CH2:8][C@@H:7]([N:9]=[N+]=[N-])[CH2:6][N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]1[CH2:8][C@@H:7]([NH2:9])[CH2:6][N:5]1[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.3 %

Procedure:
A mixture of trans-4-azido-N-tert-butoxycarbonyl-L-proline methyl ester (L, 2.00 g) and 10% palladium on activated carbon (601 mg) in methanol (60 mL) was stirred at room temperature for 2.5 hr under hydrogen. The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo to give the title compound (1.85 g) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.41-1.46 (m, 9H), 1.99-2.22 (m, 2H), 2.63 (br s, 2H), 3.13-3.35 (m, 1H), 3.67-3.79 (m, 2H), 3.73 (s, 3H), and 4.36-4.47 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34](=[O:43])[N:35]([CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42])[CH3:36])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34](=[O:43])[N:35]([CH3:36])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(CCOCCN)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C)C(=O)OC(C)(C)C
Yield: 56.5 %

Procedure:
Methyl-[2-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamic acid tert-butyl ester (69 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (82 mg), [2-(2-amino-ethoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (87 mg), HBTU (91 mg), and DIEA (52 uL).