Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.N1CCCCC1>C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])c(O)c2)S1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
To a solution of 2,4-thiazolidinedione (3.50 g, 30.0 mmol) in ethanol (120 mL) was added 3-hydroxy-4-nitrobenzaldehyde (5.00 g, 30.0 mmol) and piperidine (0.44 mL, 4.50 mmol). The mixture was stirred at reflux for 15 hours and then cooled to 0° C. The resulting precipitate was collected and washed with cold ethanol to afford 3.53 g of the desired compound as a brown solid. Further concentration and precipitation of the mother liquor afforded an additional 3.1 g of the product. This was used without further purification in the next reaction. 1H NMR (CDCl3)·8.20 (1H, d, J=8.8 Hz), 7.75 (1H, s), 7.26 (1H, s), 7.12 (1H, d, J=8.8 Hz).
Reaction SMILES: [O-]O.CC1CCC(=C(C)C)CC=1.[C:13]1([CH3:23])[CH2:18][CH2:17][C:16]([OH:22])([C:19]([CH3:21])=[CH2:20])[CH2:15][CH:14]=1>>[CH3:23][C:13]1[CH2:18][CH2:17][C:16]([OH:22])([CH:19]([CH3:20])[CH3:21])[CH2:15][CH:14]=1
Reactant: C=C(C)C1(O)CC=C(C)CC1
Agent: CC1=CCC(=C(C)C)CC1
Agent: [O-]O
Product: CC1=CCC(O)(C(C)C)CC1

Procedure:
The hydroperoxide resulting from terpinolene can be reduced to p-mentha-1,8-dien-4-ol and this can be selectively catalytically hydrogenated to give 4-terpineol.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C@@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1.CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C@@H:28]([NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH3:29])[CH:25]=[CH:26][CH:27]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: COc1cccc([C@H](C)N)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc([C@H](C)NC2=NC(=O)/C(=C/c3ccc4ncccc4c3)S2)c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(S)-(3-methoxy-phenyl)-ethylamine and DIEA to give 2-[(S)-1-(3-methoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9].[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Br:2][C:3]1[CH:11]=[C:7]([C:8]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:9])[CH:6]=[N:5][CH:4]=1
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cncc(Br)c2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.57 g (10.0 mmol) 5-bromo-nicotinic acid chloride hydrochloride, 1.49 g (10.0 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium trichloride were heated to 125° C. with stirring for 1.5 h. After cooling to RT the mixture was mixed with ice water. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#N.C(O)=[O:20]>[Ni]>[O:16]=[C:7]1[C:6]2[CH:17]=[CH:18][C:3]([CH:1]=[O:20])=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[NH:8]1
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1NC2=O
Agent: [Ni]
Product: O=Cc1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 25 °C

Procedure:
Heat a mixture of 5.0 gm. of 3-cyano-10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin and 4.0 gm. of Raney nickel alloy in 60 ml. of 75% (v/v) aqueous formic acid at reflux for 1.5 hours. Cool to room temperature and filter. Concentrate to small volume and extract with methylene chloride. Wash the extract with water and with 1 N sodium bicarbonate until neutral. Dry the neutral extract over sodium sulfate and concentrate to dryness to obtain the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][S:10]C)=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([CH2:9][SH:10]=[N:14][C:13]#[N:12])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: N#CN
Reactant: CSCc1cnc(Cl)c(F)c1
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CN=[SH]Cc1cnc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a stirred solution of 2-chloro-3-fluoro-5-methylthiomethylpyridine (1.7 g, 8.9 mmol) and cyanamide (3.7 g, 8.9 mmol) in THF (15 mL) cooled to 0° C. was added iodobenzene diacetate (2.86 g, 8.9 mmol) in one portion and the resulting mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h. The solvent was removed in vacuo and the resulting mixture was purified on silica gel using 60% acetone in hexane to give 1.828 g of [1-(5-fluoro-6-chloropyridin-3-yl)methyl]-λ4-sulfanylidenecyanamide as an off-white solid in 89% yield. LC-MS calcd. for C8H7ClFN3S [M+1]+: 232.69. Found: 232.04.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](OC2C=CC=CC=2)=[CH:6][CH:5]=1)=[O:3].[Br:17]Br>>[Br:17][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Product: O=C(CBr)c1ccccc1

Procedure:
4-Phenoxyacetophenone was brominated with bromine according to Method A to provide the desired α-bromoacetophenone, which was condensed with 2-amino-13,4,-thiadiazole-5-sulfonamide according to method C, to provide compound 87 as an off white solid. 1H NMR (200 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.71 (s, 2H), 7.90 (d, J=7.9 Hz, 2H), 7.40 (t, J=7.3 Hz, 2H), 7.07 (t, J=7.3 Hz, 1H), 7.08-7.03 (m, 6H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:25][CH2:26]2)=[O:20])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCNCC2)cc1)C(=O)NCC#N
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(S(C)(=O)=O)CC2)cc1)C(=O)NCC#N
Reaction time: 2 h

Procedure:
To a solution of N-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamide from example 17, step 7 (102 mg, 0.23 mmol) in DMF (1 mL), was added methyl sulfonyl chloride (27 μL, 0.35 mmol) and cesium carbonate (91 mg, 0.28 mmol). The mixture was aged for 2 hours under nitrogen atmosphere and was diluted with dichloromethane. The resulting mixture was filtered over celite and concentrated under reduced pressure. The crude residue was chromatographed on silica gel using 1% NH4OH and 9% methanol in dichloromethane to afford the title compound.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:29][CH2:30][O:31][CH3:32]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:29][CH2:30][O:31][CH3:32])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COCCI
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in tetrahydrofuran (9.1 mL, 9.1 mmol) under N2 at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (1.0 g, 4.1 mmol) in tetrahydrofuran (2.0 mL). The resulted light brown solution was stirred at −78° C. for 30 min before adding a solution of 1-iodo-2-methoxyethane (0.93 g, 5.0 mmol) in tetrahydrofuran (2.0 mL). The mixture was stirred for an hour at −78° C. then kept in a freezer reading at −20° C. overnight. The reaction was quenched with saturated ammonium chloride. The layers were separated and the aqueous extracted with ether three times. The combined organics were then washed with brine, dried (MgSO4), filtered and purified by flash chromatography (EtOAc/Hexane) to provide the desired product (0.28 g, 23%). LCMS calculated for C5H26NO5: (M+H) 300.2; found 300.2.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2-c2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1

Procedure:
To a solution of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine followed by stirring and heating under reflux for 2 hours. The hot reaction mixture is filtered through diatomaceous earth and the filter cake washed with hot chloroform and the filtrate concentrated in vacuo. The residue is triturated with ethyl acetate and the mixture filtered to give the desired product as crystals, m.p. 225°-228° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10].BrC1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36]([OH:38])=[O:37])[CH:27]=1.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1.CN(C=O)C.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[C:28]([C:36]([OH:38])=[O:37])[CH:27]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: O=C(O)c1cc(Br)c2ccccc2n1
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc4ccccc34)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
tert-Butyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 2) (280 mg, 0.74 mmol) was suspended in 5 ml of 4.0 M HCl in dioxane and stirred for 2 h, then evaporated in vacuo to give a brown solid, which was dissolved in 20 ml of DMF. 4-Bromoquinoline-2-carboxylic acid (188 mg, 0.74 mmol) (prepared via the procedure of Y Kato, et. al., Tetrahedron Lett 2001, 42:4849-51), and sodium bicarbonate (554 mg, 6.6 mmol) were added and the resulting solution was heated under a nitrogen atmosphere with stirring for 20 h. Upon cooling to ambient temperature, the reaction was diluted with 25 ml of water, adjusted to pH 4 using concentrated HCl, filtered and the filtrate extracted with chloroform (2×25 ml). The combined organic extract was dried over sodium sulfate and concentrated in vacuo to a yellow solid, which was suspended in 10 ml of MeOH and collected by suction filtration, to afford the title compound as a yellow solid (64 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[S-:15][C:16]#[N:17].[K+]>C(O)C>[S:15]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4])[C:16]#[N:17]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: N#CSCC(=O)c1ccc(C(F)(F)F)cc1
Yield: 95.9 %

Procedure:
A solution of 25.64 g (96.0 mmole) of 2-bromo-1-(4-trifluoromethyl-phenyl)-ethanone, 10.27 g (105.7 mmole) of potassium thiocyanate and 130 mL of ethanol (130 mL) was heated to reflux for 2 hours, and then concentrated under reduced pressure. The residue was taken up in 700 mL of ethyl acetate, washed three times with 75 mL of water, then 75 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 22.57 g of 2-thiocyanato-1-(4-trifluoromethyl-phenyl)-ethanone as an orange-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[S:11].[N+:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[C-:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:10]2[S:11][CH:21]=[N:20][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=[CH:15][CH:16]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COC(=S)c1cccc(OCc2cccc(Cl)c2)c1
Product: CCOC(=O)c1ncsc1-c1cccc(OCc2cccc(Cl)c2)c1
Yield: 77.8 %

Procedure:
In an analogous manner to that described in Example 1(C), 28.2 g (96.3 mmol) of O-methyl 3-[(3-chlorobenzyl)-oxy]thiobenzoate were reacted with ethyl isocyanoacetate and subsequently chromatographed on silica gel. Elution with 9:1, 8:2 and 1:1 mixtures of methylene chloride and ethyl acetate as well as ethyl acetate along yielded 28 g (77.8%) of ethyl 5-[3-[(3-chlorobenzyl)oxy]phenyl]-4-thiazolecarboxylate as an orange oil.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=4)[N:22]=3)[CH2:17][CH2:16]2)=[CH:9][N:8]=1)=[O:6]>CO.O>[NH2:13][C:12]1[C:7]([C:5]([OH:6])=[O:4])=[N:8][CH:9]=[C:10]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=4)[N:22]=3)[CH2:17][CH2:16]2)[N:11]=1
Reactant: COC(=O)c1ncc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2nc(N3CCC(Nc4cnc(C(=O)O)c(N)n4)CC3)nc(N)c2cc1OC
Temperature: 85 °C
Yield: 101.4 %

Procedure:
Potassium hydroxide (0.53 g, 9.46 mmol) was added to a solution of (2) (0.23 g, 0.47 mmol) in MeOH/H2O (20 mL, 10%; v/v) at 25° C. The reaction mixture was heated at 85° C. for 12 h then cooled to room temperature. The mixture was concentrated, acidified with HCl (aq) (20 mL, 3M) and the desired product was filtered and rinsed with cold H2O to give 0.21 g (93%) of the title compound: 1H NMR (DMSO) δ 12.45 (br s, 1H), 8.78 (br, 2H), 8.37 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.38 (s, 1H), 5.19 (br s, 3H), 4.56 (m, 2H), 4.13 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.41 (m, 2H), 2.04 (m, 2H), 1.54 (m, 2H); 13C NMR (DMSO) δ 167.0, 161.3, 155.8, 155.1, 154.4, 151.0, 146.7, 136.3, 121.3, 121.0, 105.2, 101.6, 99.3, 56.3, 56.0, 46.5, 43.3, 30.5; HRMS (FAB) m/z 441.1988 (M+H)+ (C20H24N8O4 requires 441.1999).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10]O)[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1CC(CS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.5 g, 1.93 mmol) and TEA (0.33 gm, 2.89 mmol) in DCM (20 ml), methane sulphonyl chloride (0.38 g, 3.86 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 4 h. Aqueous NaHCO3 solution was added to it and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to offer 4-methanesulfonylmethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow solid (0.45 g, 69%). 1HNMR (400 MHz, CDCl3): δ 1.45-1.50 (Two s, 9H); 1.79-1.85 (m, 1H); 2.42-2.81 (m, 2H); 3.08 (s, 3H); 3.21-3.38 (m, 1H); 3.77 (s, 3H); 4.09-4.4 (m, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[CH:6]=1)=[N+]=[N-]>[Pd].C(OCC)(=O)C>[N:13]1[CH:12]=[CH:11][N:8]2[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][C:7]=12
Reactant: [N-]=[N+]=NCc1ccn2ccnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCc1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 93.7 %

Procedure:
Into a round bottom flask were charged 7-(azidomethyl)imidazo[1,2-a]pyridine (1.5 g, 8.7 mmol), ethyl acetate (200 mL), and 10% Pd/C (250 mg). The mixture was stirred under hydrogen balloon at room temperature for 40 minutes. The mixture was filtered through Celite and the filtrate was concentrated to get the title product (1.2 g). 1H NMR (400 MHz, DMSO-d6): 8.48 (d, 1H, J=7.2 Hz), 7.88 (s, 1H), 7.52 (d, 1H, J=1.2 Hz), 7.51 (s, 1H), 6.89 (dd, 1H, J=7.2, 1.6 Hz), 3.83 (s, 2H).
Reaction SMILES: [C:1](NC1C=C(B(O)O)C=CC=1)(=O)C=C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)[NH:24]N=1>C(O)C.C(Cl)Cl>[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)[NH:24][CH:1]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]cc(C)c3c2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of 19 (50 mg, 0.2369 mmol) and 2 (50 mg, 0.2369 mmol) in ethanol and toluene (1:4 mL) was added sodium carbonate (49.74 mg, 0.4738 mmol). The reaction was degassed and purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (9.06 mg, 0.0114 mmol), and again degassed for 15 min. The reaction mixture was stirred for 2 h at 90° C. and the reaction mixture allowed to cool to rt and diluted with DCM (25 mL). The organic layer was filtered through Celite and concentrated to get the crude. The resulting oil was purified via silica gel chromatography using a gradient of 30% ethyl acetate:hexane to afford Compound 20. MS-ES+277 1H NMR (400 MHz, DMSO-D6) 20: 11.37 (d, 1H), 10.24 (d, 1H), 8.45 (d, 1H), 8.09 (d, 2H), 7.68 (d, 1H), 7.43 (d, 2H), 7.28 (d, 1H), 6.46 (d, 1H), 6.44 (d, 1H), 5.79 (d, 1H), 2.30 (d, 1H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CN1CCCC1=O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(O)cc1
Solvent: CN1CCCC1=O
Product: Oc1ccc(Nc2nc3ccccc3s2)cc1

Procedure:
The solution of 2-chlorobenzothiazole (2.47 mL, 20 mmol) and 4-aminophenol (2.18 g, 20.0 mmol) in N-methylpyrrolidone (16 mL) was heated at 160° C. for 7 h. The reaction mixture was quenched with aqueous 2N NaOH and then extracted with EtOAc. The organic layer was washed with 2N NaOH. To the combined aqueous layer was added aqueous 5N HCl until pH 6, then the product was extracted with EtOAc (2×), dried (Na2SO4) and concentrated. The crude product was dissolved in MeOH and treated with SiO2. Chromatography through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 50% EtOAc in hexane, provided 4-(benzo[d]thiazol-2-ylamino)phenol as a tan solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:14])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc([C@@H](N)C(C)C)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](c3cccc(C(C)C)c3)C(C)C)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-isopropylphenyl)-2-methylpropan-1-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 573 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2([C:33]([F:36])([F:35])[F:34])[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4([F:32])[CH2:31][NH:30][CH2:29]4)=[CH:24][CH:23]=3)[O:18]2)[CH:12]=[C:13]([Cl:16])[C:14]=1[F:15].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:66][S:67]([CH2:70][C:71](O)=[O:72])(=[O:69])=[O:68]>CN(C=O)C>[Cl:16][C:13]1[CH:12]=[C:11]([C:17]2([C:33]([F:34])([F:35])[F:36])[O:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4([F:32])[CH2:31][N:30]([C:71](=[O:72])[CH2:70][S:67]([CH3:66])(=[O:69])=[O:68])[CH2:29]4)=[CH:26][CH:27]=3)[O:18]2)[CH:10]=[C:9]([Cl:8])[C:14]=1[F:15]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)ON=C(c3ccc(C4(F)CNC4)cc3)O2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)O3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of trifluoroacetic acid salt of 5-(3,5-dichloro-4-fluoro-phenyl)-3-[4-(3-fluoro-azetidin-3-yl)-phenyl]-5-trifluoromethyl-[1,4,2]dioxazole (0.35 g, 0.77 mmol, 1 eq) in DMF (5 mL) was added triethyl amine (0.867 mL, 6.178 mmol, 8 eq.), followed by addition of EDC.HCl (0.22 g, 1.15 mmol, 1.5 eq), HOBt (0.104 g, 0.77 mmol, 1 eq) and methanesulfonyl-acetic acid (0.213 g, 1.54 mmol, 2 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (3×30 mL). Combined organic phase was washed with saturated solution of LiCl solution (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.51 g, Crude). Crude was purified by combiflash using 40 g Redisep column. Desired compound was eluted in 47% ethyl acetate in hexane to afford title compound as off white solid (0.225 g, 50.82%). 1H NMR (400 MHz, CDCl3) δ: 3.17 (s, 3H), 3.87 (s, 2H), 4.37-4.45 (m, 1H), 4.52-4.60 (m, 1H), 4.80 (d, J=19.64 Hz, 2H), 7.61-7.65 (m, 4H), 7.91 (d, J=8.24 Hz, 2H), LC-MS (m/z): 571.0 (M−H), HPLC Purity: 93.59%.