Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine following a procedure analogous to that described for Intermediate 10. LC (method 3): tR=1.10 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:14]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)#[N:15].O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCOc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
15.0 g of PPE, 4.00 g (22.4 mmol) of the compound (12) and 2.66 g (22.3 mmol) of p-cyanophenol were dissolved in ml of chloroform under an argon gas atmosphere and the whole was stirred at room temperature overnight. After addition of water to the reaction mixture, the whole was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 4.80 g of p-cyanophenyl p-allyloxybenzoate (17) as a white solid (yield: 76.7%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:12]1[C:16]2([CH2:21][CH2:20][CH:19]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([I:1])=[N:3]3)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: OC1CCC2(CC1)OCCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate LA) (11 g, 0.042 mol) was suspended in tetrahydrofuran (500 mL) at room temperature under a nitrogen atmosphere. A solution of 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (19.98 g, 0.126 mol) in tetrahydrofuran (50 mL) and subsequently triphenylphosphine (22.1 g, 0.084 mol ) was added to the suspension. The suspension was cooled to 0° C. and then diethyl azodicarboxylate (14.67 g, 0.084 mol) was added slowly. After stirring the reaction mixture at 0° C. for 15 min, it was allowed to warm to room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300-400 mL) and allowed to stand overnight. A precipitate formed which was collected by filtration, washed with ethyl acetate, and dried on the lyophilizer to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a pale yellow solid (54%, 9.12 g, 0.023 mol): 1H NMR (DMSO-d6, 400 MHz) 8.19 (s, 1H), 4.70 (m, 1H), 3.90 (m, 4H), 2.13 (m, 2H), 1.74 (m, 6H). TLC (dichloromethane/methanol=9:1) Rf 0.61.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[Br:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.[BH4-].[Na+]>CCO.CO>[Br:11][C:12]1[S:16][C:15]([CH2:17][NH:10][C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: Nc1cc(F)c(F)cc1F
Reactant: O=Cc1ccc(Br)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Fc1cc(F)c(NCc2ccc(Br)s2)cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 2 g (13.6 mmol) of 2,4,5-trifluorophenylamine and 2.66 g (13.9 mmol) of 5-bromothiophene-2-carbaldehyde in 30 ml of EtOH, 9.4 g of molecular sieves (0.3 nm) were added and the mixture was refluxed for 20 hours. After this time the reaction mixture was cooled to room temperature, filtered and the solvent was evaporated in vacuo. The oil obtained was dissolved in 30 ml of MeOH and 0.51 g (13.6 mmol) of NaBH4 were added in small portions, maintaining the temperature of the reaction at room temperature. The mixture was stirred at this temperature for 20 more hours. After this time the solvent was evaporated in vacuo and the residue was treated with 100 ml of water and extracted twice with ether. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to give 3.2 g of an oil. This 3.2 g were combined with 3.5 g obtained in a subsequent preparation and the total product obtained (6.7 g) was purified by chromatography on silica gel using mixtures of hexane/AcOEt 5:1→1:1 as eluent Appropriate fractions were combined to give 0.95 g of the title product as an oil. (global yield 8.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OCCCO2)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.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.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2ccccc2Br)CC1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2ccccc2-c2cccnc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
After dissolving 575 mg of 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-bromophenyl)ethanone in 10 ml of N,N-dimethylformamide, there were added 489 mg of 2-(3-pyridyl)-1,3,2-dioxaborinane, 173 mg of tetrakis(triphenylphosphine)palladium(0) and 1.47 g of anhydrous cesium carbonate, and the mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (379 mg, 66% yield).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]([Cl:28])[C@H:13]3OS(C)(=O)=O)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C([O-])(=O)C.[K+].CS(C)=O>O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C:14]([Cl:28])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](OS(C)(=O)=O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.1 %

Procedure:
A mixture of 2.35 g of 17α-acetoxy-6β-chloro-7α-mesyloxy-2-oxa-4-pregnene-3,20-dione, 0.83 g of potassium acetate and 0.88 ml of dimethyl sulfoxide was stirred at room temperature for 12 hours. Ice-cooled water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 1.37 g of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione. The 1H NMR spectrum of this compound was the same as that of the compound produced in Example 1.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccccc1
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 71 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and phenylhydrazine according to the method described for Example 1 in 71% yield. MS: M=345.1 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCNc1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (35 mg, 0.077 mmol) and methoxyethylamine (5 eq) in DMF (0.5 ml) was added K2CO3 (5 eq). The mixture was stirred for 12 hours at 110° C. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (10 mg, 26%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:9]=1.[N+:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]>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.C1(C)C=CC=CC=1>[N+:26]([C:29]1[CH:34]=[C:33]([C:8]2[CH:25]=[CH:24][C:11]([O:12][CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:10][CH:9]=2)[CH:32]=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
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+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 110 °C
Yield: 59.9 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.31 g) ethanol (1 ml), 3-nitrobenzeneboronic acid (0.24 g) and tetrakis(triphenylphosphine)palladium(0) (30 mg) with heating at 110° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give (2R)-1-(3'-nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol as a yellow oil (0.210 g). Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic acid gave the title compound as a hygroscopic gum (0.150 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.CCCCCC.[O:18]=[C:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[NH4+]>C1COCC1>[OH:18][C:19]([C:4]1[S:3][C:2]([CH3:1])=[N:6][CH:5]=1)([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1cnc(C)s1
Reaction time: 0.5 h

Procedure:
To a solution of 1.5 g of 2-methyl-1,3-thiazole in 20 ml of THF was added 5.5 ml of a 2.76 M n-butyllithium/hexane solution at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added dropwise a solution of 2 ml of ethyl 2-oxopropanoate in 10 ml of THF, followed by stirring at −78° C. for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.05 g of ethyl 2-hydroxy-2-(2-methyl-1,3-thiazol-5-yl)propanoate.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+].COC1C=C(OC)C=CC=1C[N:25]1[C@H:28]([CH:29]=[N:30][O:31][CH3:32])[C@H:27]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[C:26]1=[O:44]>C(#N)C.O.C(OCC)(=O)C>[CH3:32][O:31][N:30]=[CH:29][C@H:28]1[NH:25][C:26](=[O:44])[C@H:27]1[NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]
Reactant: CON=C[C@@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CON=C[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: 78 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
11.9 g (44 mmol) of potassium peroxydisulphate and 9.6 g of dipotassium hydrogen phosphate are dispersed in 110 ml of acetonitrile and 350 ml of water. The mixture is heated to 78° C. and a solution of 11.8 g (27.6 mmol) of benzyl (3S, 4S)-1-(2,4-dimethoxybenzyl)-4-[(methoxyimino)-methyl]-2-oxo-3-azetidinecarbamate (mixture of the E and Z isomers) in 300 ml of acetonitrile is added dropwise thereto. The pH of the solution is held at 7 by the addition of dipotassium hydrogen phosphate. After boiling for 6 hours, the mixture is cooled, the aqueous phase is discarded, the organic phase is diluted with ethyl acetate and washed successively with water, aqueous sodium bicarbonate solution and sodium chloride solution. After drying over sodium sulphate, the solvent is removed by evaporation and the crude mixture is chromatographed [230-400 mesh, ethyl acetate/n-hexane (8:2)], there being obtained 1.7 g (27%) of benzyl (3S, 4S)-4-[(methoxyimino)methyl]-2-oxo-3-azetidinecarbamate (mixture of the E and Z isomers); melting point 170°-171° C.
Reaction SMILES: S(Cl)([Cl:3])=O.C(OC([NH:12][C@@:13]1([C:32]([O:34][C:35](C)(C)[CH3:36])=[O:33])[CH2:18][C@@H:17]([S:19][C:20]2[NH:24][CH:23]=[N:22][N:21]=2)[C@@H:16]2[C@H:14]1[C@H:15]2[C:25]([O:27][C:28](C)(C)[CH3:29])=[O:26])=O)(C)(C)C>C(O)C>[ClH:3].[NH2:12][C@@:13]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:18][C@@H:17]([S:19][C:20]2[NH:24][CH:23]=[N:22][N:21]=2)[C@@H:16]2[C@H:14]1[C@H:15]2[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Reactant: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Product: Cl

Procedure:
Add thionyl chloride (2.5 mL, 34.32 mmol) to a stirred solution of ditert-butyl (1R,2S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.1 g, 4.23 mmol) in ethanol (40 mL) at 0-5° C. dropwise over 5 minutes with caution (exothermic reaction). Remove the cooling bath and heat the reaction mixture at reflux temperature for 16 hours. Evaporate the volatiles and dry the residue under high vacuum for 7 hours to obtain a colorless foam of diethyl (1R,2S,4R,5R,6R)-2-amino-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride. Add then 2-(tert-butoxycarbonylamino)acetic acid (0.89 g, 5.07 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.93 g, 5.07 mmol) to a solution of diethyl (1R,2S,4R,5R,6R)-2-amino-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride in anhydrous N,N-dimethylformamide (20 mL) at room temperature then add diisopropylethylamine (2 mL, 11.47 mmol) and stir the resulting yellow solution under nitrogen for 18 hours. Concentrate the solvent and partition the residue between ethyl acetate (40 mL) and a saturated solution of sodium hydrogen carbonate in water (40 mL). Stir the mixture for 20 minutes, separate the layers and extract the aqueous layer with more ethyl acetate (40 mL). Combine the organics layers, dry on sodium sulfate and concentrate to dryness. Purify the residue by flash chromatography eluting with ethyl acetate: iso-hexane (80:20 to 100:0) to give the title compound as a colorless solid (2.42 g, 4.86 mmol). MS (m/z): 498 (M+1), 520 (M+23).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([CH2:32]Br)=[CH:27][C:26]=1[Cl:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:24][C:25]1[C:26]([Cl:34])=[CH:27][C:28]([CH2:32][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:29][C:30]=1[Cl:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: Clc1cc(CBr)cc(Cl)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2cc(Cl)c(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and 2-benzyloxy-5-bromomethyl-1,3-dichloro-benzene (CAB02118, 1.73 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (2×100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.76 g (78%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].CCN(CC)CC.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C=O
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A solution of (3-methyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (1.613 g, 6.060 mmol) in dimethylsulfoxide (DMSO, 12.0 mL) is treated with Et3N (5.50 mL, 39.460 mmol) and pyridine-sulfur trioxide (2.902 g, 18.235 mmol) in a cold water bath. The bath is removed after 3 min. and the reaction is stirred overnight. The reaction mixture is poured into H2O (50 mL) and extracted with EtOAc (3×50 mL). Combined organic extracts are dried over MgSO4, filtered, and conc. The residue is loaded onto silica gel and eluted with hexanes using a gradient from 5% EtOAc to 33% EtOAc to provide 3-methyl-4′-trifluoromethyl-biphenyl-4-carbaldehyde (1.221 g, 76%) as white crystals.
Reaction SMILES: C=O.[BrH:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.[C:12]1(C)C=CC=CC=1>>[Br:3][CH2:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1ccccc1
Reactant: Br
Agent: C=O
Product: Clc1ccc(SCBr)cc1
Reaction time: 1 h

Procedure:
To a slurry of paraformaldehyde (36.24 g, 1.21 mol, 1.58 equiv) in toluene (243 ml) at 22° is added aqueous hydrobromic acid (48.5 wt %, 652 ml, 5.86 mol, 7.68 equiv) with an endotherm to 18°. The resultant biphasic solution is warmed to 40° and a solution of 4-chlorothiophenol (VII, 138.81 g, 0.960 mol, 1.26 equiv) in toluene (116 ml) is added over ½ hour while maintaining 40-43° and rinsed in with toluene (50 ml). The mixture is then warmed to 50° and stirred 1 hour. The mixture is cooled to 10°, the phases separated, and the aqueous washed with toluene (250 ml). The combined organics are treated with ice water (500 ml), hexanes (350 ml) and the phases separated. The aqueous phase is then washed with toluene (200 ml) and the combined organic phases are dried over magnesium sulfate and concentrated to give crude bromomethylthio-4-chlorobenzene (268.01 g), NMR 7.43, 7.34, 4.79 δ; CMR 134.37, 132.05, 131.78, 129.46, 37.32 δ; HRMS (EI+) calculated for C7H6BrClS=235.9063, found =235.9063.
Reaction SMILES: C[O:2][B:3]([O:6]C)OC.Br[C:9]1[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=1)[C:14]#[N:15].C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[C:14]([C:13]1[CH:16]=[C:9]([B:3]([OH:6])[OH:2])[CH:10]=[CH:11][C:12]=1[F:17])#[N:15]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1cc(B(O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Trimethylborate (1.37 mL, 12 mmol) was added to a solution of 5-bromo-2-fluorobenzonitrile (2.0 g, 10 mmol) in toluene (16 mL) and THF (4 mL) at −78° C. n-Butyl lithium (2.5M in hexane; 4.8 mL) was slowly added over 1 h and the solution was stirred for 30 min after which it was warmed to rt for 1 h. The reaction was cooled to 0° C. and quenched with 20 mL of 1 N HCl. The product was extracted with ethyl acetate (2×200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 5% methanol/methylene chloride afforded 0.33 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:27])(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([O:14][CH3:27])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)OC(C)(C)C)CC1O
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CC1N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
A suspension of Compound G (52 g, 0.16 mol) in THF (150 mL) was stirred at RT for about 30 min and cooled to −10 to −15° C. A solution of potassium hexamethyldisilylamide (KHMDS, 40 solution in THF, 144 mL, 0.256 mol) was slowly added while controlling the temperature between −5 and −15° C. After 15 min, dimethyl sulfate (18.7 mL, 1.20 mol) was added dropwise to the reaction mixture while maintaining a temperature between −10 and 0° C., and the resulting reaction mixture was then stirred at this temperature for about 30 min. The reaction mixture was quenched by the addition of water (100 mL), followed by acetic acid (50 mL). The product was extracted with methyl tert-butyl ether (2×150 mL). The combined organic layer was washed with water (100 mL), brine (50 mL) and dried over anhydrous Na2SO4. Evaporation under reduced pressure gave Compound H as an oil (54 g).