Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13]O)[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24]COCC[Si](C)(C)C)=[C:20]([O:33][CH3:34])[CH:19]=3)=[O:16])=[N:9]2)=[CH:4][CH:3]=1.CS([Cl:39])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:39][CH2:13][C:11]1[C:10]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:33][CH3:34])[CH:19]=2)=[O:16])=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: COc1cc(NC(=O)c2nn(-c3ccc(Cl)cc3)cc2CO)ccc1OCOCC[Si](C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2nn(-c3ccc(Cl)cc3)cc2CCl)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.9 %

Procedure:
To a mixture of 1-(4-chlorophenyl)-4-(hydroxymethyl)-N-(3-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazole-3-carboxamide (2.11 g, 4.19 mmol) in CH2Cl2 (40 mL) at room temperature under Ar was added methanesulfonyl chloride (0.424 mL, 5.44 mmol) and triethylamine. (1.20 mL, 8.61 mmol). The resulting solution was stirred at room temperature for 1.5 h. Solvent was evaporated. The crude product was diluted with EtOAc (150 mL), washed with H2O (30 mL). The organic layer was separated, dried over MgSO4 and concentrated to give a crude product which was further purified by ISCO automated chromatography (110 g, Hexane/EtOAc, 100:0 to 50:50 gradient) to give the products as beige solid (0.721 g, 44% yield). SEM group was deprotected during the process. LCMS (ES): m/z 392.0 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:32][C:33]([F:47])([F:46])[C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:45])[CH2:41][C:42](=O)[CH3:43])=[CH:36][CH:35]=1>>[CH:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([NH:1]/[C:42](/[CH3:43])=[CH:41]\[C:40](=[O:45])[C:37]4[CH:38]=[CH:39][C:34]([C:33]([F:32])([F:46])[F:47])=[CH:35][CH:36]=4)[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=3)[N:17]=2)=[CH:27][CH:26]=1)([CH3:31])[CH3:30]
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1ccc(C(F)(F)F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.18 mmol) of Intermediate 51 and 41 mg (0.18 mmol) of Intermediate 24 to yield 48 mg (43% yield) of Example 3: TLC (DCM/MeOH, 4/1): Rf=0.42; 1H NMR (DMSO-d6, 400 MHz) δ11.5 (d, 1H, J=8.9), 7.95 (d, 2H, J=7.2), 7.77 (d, 2H, J=8.7), 7.72 (d, 2H, J=8.2), 7.1 (d, 2H, J=8.4), 6.97 (d, 2H, J=8.9), 6.79 (d, 2H, J=8.5), 5.58 (s, 1H), 4.65 (m, 1H), 4.11 (t, 2H, J=6.5), 4.1 (m, 1H), 3.16 (dd, 1H, J=13.7, 3.6), 2.84 (t, 2H, J=6.5), 2.74 (dd, 1H, 13.7, 9.0), 2.28 (s, 3H), 1.67 (s, 3H), 1.25 (d, 6H, J=6.0); low resolution MS (ES+)m/e 637.1 (MH+);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][CH3:12])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:13].Cl[C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:10]([O:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]2[C:5]([CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[O:13]2)=[CH:6][CH:7]=1)[CH2:11][CH3:12]
Reactant: C#CC(C)(C)Cl
Reactant: CCCOc1cccc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc2c(c1OC)OC(C)(C)C=C2
Reaction time: 20 h
Yield: 79.2 %

Procedure:
A suspension of 5.5 g (30 millimoles) of 2-methoxy-3-n-propoxy-phenol, 6.5 g (60 millimoles) of 3-chloro-3-methyl-but-1-ine, 5 g of potassium carbonate, 8 g of potassium iodide and 50 ml of anhydrous acetone is heated to boiling under stirring for 20 hours. The inorganic salt is filtered off, the filtrate evaporated and the residue heated to boiling in 100 ml of N,N-dimethyl aniline for 8 hours. The reaction mixture is worked up in the usual manner and the product is purified as described in Example 3. Thus 5.9 g of the title compound are obtained in the form of a colorless oil, yield 80%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH2:6][NH:5]2.[N+:14]([O-])([OH:16])=[O:15]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2
Reactant: O=[N+]([O-])O
Reactant: O=C1CNc2cc(Br)c(Cl)cc2N1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred suspension of 6-bromo-7-chloro-3,4-dihydroquinoxaline-2(1H)-one (0.06 g, 0.23 mmol, as obtained above) in CF3COOH (0.5 mL) was added fuming HNO3 (0.02 mL, 0.46 mmol) and the resulting reddish yellow suspension was stirred at room temperature overnight. The cream colored suspension so obtained was poured into ice (2.5 mL) and the precipitated solid was filtered, washed with water (1.0 mL), and dried under vacuum to afford 0.049 g (70%) of the title compound as a cream colored powder. 1H NMR (DMSO-d6): δ 7.577 (s, 1H), 8.251 (s, 1H), 12.879 (s, 1H). The crude product was used as such for the final reaction.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:2]=[CH2:3]>C(O)C.[Pd]>[CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:21])[CH3:22])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:2][CH3:3]
Reactant: C=CCc1c(OCC(=O)OCC)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(OCC(=O)OCC)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Ethyl [[7-allyl-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazol-6-yl]oxy]acetate (65 mg, 0.12 mmol) was dissolved in ethanol (7.0 mL). To the solution, 10% Pd—C (6 mg) was added. The mixture was stirred for 3 hours under hydrogen atmosphere (and ordinary pressure). After insoluble was filtered off, the filtrate was condensed to give the desired compound (63 mg) as colorless oil in the residue (yield 97%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([NH:18][C:19](=[O:40])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:28](=[O:39])[C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=4)[CH:21]=3)=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[O:35][CH3:36])[C:28]([NH:27][CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19](=[O:40])[NH:18][C:12]2[CH:13]=[N:14][C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[CH:11]=2)[CH:21]=1)=[O:39]
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3cnc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3cnc4c(c3)CNCC4)c2)cc1OC
Reaction time: 8 h
Yield: 102.5 %

Procedure:
Dissolved 3-{3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoylamino}-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (120 mg, 0.22 mmol) in 3 mL CH2Cl2 and added HCl in dioxane (1.00 mL/4.0 mmol). The mixture was stirred overnight resulting in a heterogenous mixture. Concentrated the mixture to dryness to give 100.7 mg of the desired product. MS, electrospray 447.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O>[Pd].C(O)C>[NH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccncc1N
Reaction time: 48 h
Yield: 0.1 %

Procedure:
A mixture of 0.475 g (3.08 mmol) of 4-methoxy-3-nitropyridine (Org. Process Res. Dev. 2004, 8, 903-908) and 0.301 g (2.84 mmol) of 10% palladium on carbon in ethanol (30 mL) was stirred under an atmosphere of hydrogen for 48 hrs. The catalyst was removed by filtration through a pad of celite, and the solvent was removed to give 0.380 mg (99%) of 3-amino-4-methoxypyridine as a pink powder, which was used in the next step without further purification: 1H NMR (DMSO-d6) δ8.09 (dd, J=6.4, 1.2 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.36 (d, J=6.4 Hz, 1H), 6.01 (br s, 2H), 4.06 (s, 3H).
Reaction SMILES: [CH2:1]([C@H:3]1[O:8][C@:7]([C@@H:10]2[CH2:14][S:13][C:12](=[O:15])[N:11]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([OH:9])[CH2:6][C@H:5]([OH:25])[CH2:4]1)[CH3:2].O[C@:27]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@@H](O)C[C@@H](CCCC=C)O1>>[CH2:1]([C@H:3]1[O:8][C@:7]([C@@H:10]2[CH2:14][S:13][C:12](=[O:15])[N:11]2[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)([O:9][CH3:27])[CH2:6][C@H:5]([OH:25])[CH2:4]1)[CH3:2]
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: CC[C@@H]1C[C@@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Product: CC[C@@H]1C[C@@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1

Procedure:
Application of the method shown in Example 13, with the modification that (R)-4-((2R,4R,6R)-6-ethyl-2,4-dihydroxy-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].Cl[C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:22]=[C:16]2[CH:17]=1
Reactant: Nc1cc(Br)cc[n+]1N
Reactant: CCOC(=O)C(=O)Cl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2cc(Br)ccn2n1
Yield: 60.3 %

Procedure:
A mixture of 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (4.18 g, 10.8 mmol) and ethyl 2-chloro-2-oxoacetate (2.4 ml, 21.5 mmol) in pyridine (25 ml) is heated for 18 hours to 100° C. The solvent is evaporated and the orange residue triturated with sat. aqueous sodium hydrogencarbonate solution for 2 hours. The solid is collected by filtration, washed several times with water and dried affording ethyl 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.759 g, 60.5%) as a light pink solid. mp.: 158-160° C. MS: m/z=270.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:27])[N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCNCC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Product: CCN(CC)C(=O)CN(c1ccccc1C(N)=O)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with diethylamine
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:56][CH:57]=1
Reactant: COc1ccc(-c2cccc(N)c2)cc1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
DIEA (0.0144 mL, 0.083 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.017 g, 0.075 mmol) and HATU (0.032 g, 0.083 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-biphenyl-3-ylamine (0.015 g, 0.075 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 68% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[C:16]#[N:17].[CH2:18]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[C:16]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:26]1[CH2:25][CH2:24][N:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])[CH2:28][CH2:27]1)#[N:17]
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c(C#N)c1
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2C#N)CC1

Procedure:
1.5 g (6.1 mmol) of the chlorocyanophenylpyridazinone from stage (a) and 5 ml of 1-ethoxycarbonylpiperazine are together heated to 170° C. for 5 hours. After the reaction mixture has cooled, it is poured out on water and extracted with ethyl acetate and the combined organic phases are concentrated by evaporation under vacuum.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].[NH4+].[Cl-]>CCOCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccncc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Temperature: -30 °C

Procedure:
To a suspension of 4-bromopyridine hydrochloride (1.5 g) in Et2O (20 mL) at -78° C. was added n-BuLi (6.2 mL of a 2.5M solution). After 30 min. the mixture was warmed to -30° C., tributyltin chloride (2.1 mL) was added and the mixture warmed to 0° C. Saturated NH4Cl was added and extracted with Et2O. The organics were washed with H2O, brine, dried (MgSO4) and concentrated. Chromatography (silica gel; EtOAc/hexane (15:85)) provided the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1.CN(C)C=O.C1CCN2C(=NCCC2)CC1>C1COCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[CH2:21][S:27][C:28]1[CH:29]=[CH:30][C:31]([S:34](=[O:36])(=[O:35])[NH2:37])=[CH:32][CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Reactant: NS(=O)(=O)c1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CSc1ccc(S(N)(=O)=O)cc1
Reaction time: 7 h
Yield: 42.9 %

Procedure:
To a liquid mixture of a solution of (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-mesyloxymethylpyrrolidine (5.02 g, 12.3 mmol) and p-mercaptobenzenesulfonamide (2.39 g, 12.6 mmol) in THF (60 ml) with -N,N-dimethylformamide (20 ml), 1,8-diazabicyclo[5.4.0]-7-undecene (2.46 ml, 16.4 ml) was added dropwise in a nitrogen stream at room temperature. The reaction solution was stirred at the same temperature for 7 hours and then poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (Wakogel™ C-300 heptane-ethyl acetate 9:1→4:1→3:2) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-sulfamoylphenyl)thiomethylpyrrolidine (2.65 g, yield: 43.1%) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH2:39][CH:40]=[CH2:41])[CH:30]=[C:31]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH:32]=1)=[O:27])[CH3:24]>C1COCC1>[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH2:39][CH:40]=[CH2:41])[CH:30]=[C:31]([C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:38])[C:34]([F:36])([F:35])[F:37])[CH:32]=1)=[O:27])[CH3:24]
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: C=CCn1cc(C(=O)C(F)(F)F)cc1C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (2.0 g, 6.8 mmol, 1.2 equiv.) in 20 mL of THF was added n-BuLi (2.5 mL, 6.2 mmol, 1.1 equiv.) followed by a chilled (−78° C.) solution of 1-allyl-4-(2,2,2-trifluoroacetyl)-1H-pyrrole-2-carboxylic acid ethyl ester (1.6 g, 5.7 mmol, 1.0 equiv.) in 3 mL of THF in one portion. After 30 minutes, the mixture was quenched with water, warmed to room temperature, diluted with brine, and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5-30% EtOAc-hexanes) to provide 890 mg (32%) of the title compound as a pale orange solid. MS m/z 488.30 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]#[N:11])=[C:4]([S:12][CH3:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([S:12]([CH3:13])=[O:22])[C:5]([C:10]#[N:11])=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CSc1nc(N)nc(SC)c1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CSc1nc(N)nc(S(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask were added 2-Amino-4,6-bis-methylsulfanyl-pyrimidine-5-carbonitrile (7:212 mg, 1 mmol, 1.0 eq.), m-chloroperbenzoic acid (2 mmol), and dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 1 hr. The precipitate was filtered and gave to white solid. No further purification was necessary (282 mg). LC-MS: (ES+) m/z 229 (M+1). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 2.85 (s, 3H), 2.47 (s, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Br[C:27]1[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:24][N:21]1[CH2:22][CH2:23][C@H:19]([O:18][C:16]2[CH:15]=[C:4]([CH:3]=[C:2]([O:1][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:17]=2)[C:5]([NH:7][C:8]2[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[O:6])[C:20]1=[O:25]
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 40 %

Procedure:
A mixture 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (305 mg, 0.6 mmol), 5-bromo-2-methylsulfonyl-pyridine (CAS no. 98626-95-0) (142 mg, 0.6 mmol), cesium carbonate (390 mg, 1.2 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (112 mg, 0.12 mmol) in N,N-dimethylacetamide (5 mL) was stirred in the microwave at 160° C. for 6 hours. N,N-Dimethylacetamide was removed by evaporation under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and water (50 mL). The organic phase was separated and the aqueous layer was acidified with hydrochloric acid (1N, 5 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-5% methanol in DCM to afford the product (120 mg, 40%). 1H NMR δ (300 MHz, CDCl3) 2.14-2.32 (m, 1H), 2.52-2.69 (m, 1H), 2.55 (s, 3H), 2.94 (s, 3H), 3.23 (s, 3H), 3.35-3.59 (m, 2H), 4.96 (t, 1H), 7.05 (s, 1H), 7.27 (s, 1H), 7.48 (d, 1H), 7.54 (s, 1H), 8.07 (d, 1H), 8.14 (s, 1H), 8.49 (s, 1H), 8.55 (s, 1H), 9.51 (s, 1H); m/z 498 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22]C(=O)C)[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OC(C)=O)c2)CCCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
The compound of step 1 (10.6 g, 29.4 mmol) was dissolved in methanol (100 ml), potassium carbonate (812 mg, 5.88 mmol) was added and the mixture was stirred overnight at room temperature. An excess of 2 N hydrochloric acid was added, the methanol was evaporated in vacuo and the residue partitioned between EA and water. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to give the title compound (6.81 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].Br[C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:13]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Product: COc1cccc(C(=O)c2ccc(OC)cc2C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 3-methoxybenzoyl chloride and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:23]([C:22]([F:21])([F:36])[F:37])[CH:24]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2-methoxy-[3,4]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow foam (21%). MS (ESI): m/z=524.100 [M+H]+.