Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([OH:11])=[O:24])=[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1
Reactant: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
An aqueous solution (2 ml) of sodium dihydrogenphosphate (157 mg, 1.31 mmol), an aqueous solution (7 ml) of sodium chlorite (795 mg, 80%, 7.07 mmol) and aqueous hydrogen peroxide (0.5 ml, 30%) were added to an acetonitrile solution (5 ml) of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (735 mg, 1.69 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous 10% sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (603 mg, 1.33 mmol, 79%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:56])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:55])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4([C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:58])[CH3:57])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61].CC#N>ClCCl>[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61].[OH2:4].[Cl:54][C:51]1[CH:50]=[CH:49][C:48]([C:45]2([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]34[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]3[C@@H:25]3[C@@:20]([CH3:55])([CH2:21][CH2:22]4)[C@@:19]4([CH3:56])[C@@H:28]([C@:29]5([CH3:32])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:58])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:59])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)[CH2:47][CH2:46]2)=[CH:53][CH:52]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccc(Cl)cc3)CC2)CC1=O
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccc(Cl)cc3)CC2)CC1=O
Product: O
Yield: 58.5 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (460 mg, 0.554 mmol) in Dichloromethane (6 mL) was added TFA (3 mL, 0.554 mmol). The reaction mixture was stirred at r.t for 2 hs and evaporated in vacuo to afford crude product, which was purified by preparative-HPLC (Mobile Phase: A=0.05% TFA/H2O, B=MeCN) to give the product 4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (130 mg, 0.162 mmol, 29.2%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.00 (m, 1H), 7.31 (d, J=8.8 Hz, 2H), 7.15 (d, J=15.6 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 5.99 (d, J=15.6 Hz, 1H), 4.56 (m, 1H), 3.11 (m, 1H), 2.89-0.80 (m, 54H); LC/MS: m/z calculated 773.4. Found 774.3 (M+1)+.
Reaction SMILES: C([O:8][N:9]1[CH:12]([CH2:13][O:14]CC2C=CC=CC=2)[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]1=[O:40])C1C=CC=CC=1.[H][H]>CO.[Ni]>[OH:8][N:9]1[CH:12]([CH2:13][OH:14])[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]1=[O:40]
Reactant: O=C(Nc1ncnc2c1ncn2C1C(=O)N(OCc2ccccc2)C1COCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: O=C(Nc1ncnc2c1ncn2C1C(=O)N(O)C1CO)c1ccccc1

Procedure:
1-N-Benzyloxy-3-(N-benzoyladenin-9-yl)-4-benzyloxymethyl-2-azetidinone (10 mmole) is taken up in methanol (50 ml) and hydrogenated using Raney nickel (5 g) and hydrogen at a pressure of 40 psi for 6 hours. The reaction mixture is filtered, the catalyst washed with methanol (20 ml) and the combined methanol fractions are concentrated to give the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH3:24])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:24])[C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:36])([F:37])[F:25])=[CH:32][CH:31]=3)=[O:35])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1)OCC
Temperature: 50 °C
Yield: 97.6 %

Procedure:
A mixture of 1 g (3 mmol) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate (prepared according to Example 43b) and 0.8 mL (6 mmol) of 4-trifluoromethylphenyl isocyanate is placed in a sealed tube and heated at 50° C. for 15 hours. The reaction medium is cooled and the residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.5 g (95%) of ethyl (Z)-2-ethoxy-3-{3′-[1-methyl-3-(4-trifluoromethylphenyl)ureido]biphenyl-4-yl}acrylate are obtained in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5]([N:31]([CH3:32])[CH3:30])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1ccc(Cl)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 160 °C
Yield: 201.8 %

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (188 mg, 0.46 mmol) was placed in a microwave vial and dissolved in THF (4 ml). Dimethylamine (0.463 ml, 0.93 mmol) and DIPEA (0.485 ml) were added and the mixture was heated at 160° C. for 1 h under microwave irradiation. The solvent was removed in vacuo and the yellow residue was dissolved in DCM (10 ml) and washed with water (10 ml). The DCM was removed in vacuo and the solid was dried in vacuo on a high vacuum line to afford the title compound (400 mg) as a yellow solid.
Reaction SMILES: CN1CCN=C1C1C=CC([NH:13][C:14]([C@H:16]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][N:17]2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[O:27])=[O:15])=CC=1.ClC1C=CC(NC(C2C3C(=CC=CC=3)CC(C(O)=O)N2)=O)=CC=1.[N:59]1([CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[CH2:64][CH2:63][CH2:62][CH2:61][C:60]1=[O:65].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[N:59]1([CH:66]2[CH2:71][CH2:70][N:69]([CH:18]3[C:19]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:25][CH:16]([C:14]([NH2:13])=[O:15])[N:17]3[C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[O:27])[CH2:68][CH2:67]2)[CH2:64][CH2:63][CH2:62][CH2:61][C:60]1=[O:65]
Reactant: O=C1CCCCN1C1CCNCC1
Reactant: CN1CCN=C1c1ccc(NC(=O)[C@H]2Cc3ccccc3CN2C(=O)Nc2ccc(Cl)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C1Cc2ccccc2C(C(=O)Nc2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1Cc2ccccc2C(N2CCC(N3CCCCC3=O)CC2)N1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R) 2N-(4-chlorophenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (50 mg, 0.15 mmol), 4-(2-piperidinon-1-yl) piperidine (20 mg, 0.11 mmol) and triethylamine (30 uL, 0.22 mmol) in DMF (3 mL), BOP (70 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for 30 min. It was then purified by HPLC to give the titled compound (31 mg). MS 495.2 and 497.2 (M+H, Cl pattern).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([OH:35])=O)[CH2:30][CH:29]1[CH:31]=[CH2:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]([C:40]1([O:43][S:44](=[O:47])(=[O:46])[NH2:45])[CH2:42][CH2:41]1)([CH3:39])[CH3:38].C1(OS(=O)(=O)N)C=CC=CC=1.C(C1(O)CC1)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:45][S:44]([O:43][C:40]2([CH:37]([CH3:39])[CH3:38])[CH2:42][CH2:41]2)(=[O:47])=[O:46])=[O:35])[CH2:30][CH:29]1[CH:31]=[CH2:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C1(OS(N)(=O)=O)CC1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C1(O)CC1
Agent: NS(=O)(=O)Oc1ccccc1
Product: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1(C(C)C)CC1

Procedure:
2-[1-(1-Isopropyl-cyclopropoxysulfonylaminocarbonyl)-2-vinyl-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according the method presented in the synthesis of Compound 51. Treatment of 2-(1-carboxy-2-vinyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester with sulfamic acid 1-isopropyl-cyclopropyl ester, synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 utilizing 1-isopropyl cyclopropanol, yielded the desired sulfamic ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])C.O.[NH2:19][NH2:20].COC(OC)OC.[F:28][C:29]([F:43])([F:42])[C:30]1[N:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:33]2=[N:32][N:31]=1>C(O)C>[F:14][C:13]([F:16])([F:15])[O:12][C:6]1[CH:7]=[CH:8][C:9]([C:36]2[CH:37]=[CH:38][C:33]3[N:34]([C:30]([C:29]([F:43])([F:42])[F:28])=[N:31][N:32]=3)[CH:35]=2)=[CH:10][C:5]=1[C:4]1[O:3][CH:1]=[N:19][N:20]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(Br)ccc1OC(F)(F)F
Reactant: OB(O)c1ccc2nnc(C(F)(F)F)n2c1
Solvent: COC(OC)OC
Solvent: O
Solvent: CCO
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1-c1nnco1

Procedure:
To a round bottom flask was added ethyl-5-bromo-2-(trifluoromethoxy)benzoate (0.638 mmole) in ethanol (10 mL). To this solution was added 1 mL of hydrazine monohydrate and the resulting mixture was refluxed overnight. The reaction mixture was evaporated in vacuo to give A. To A was added trimethylorthoformate in a heavy wall pressure tube. This resulting mixture was heated at 100 C for 18 hours. The reaction mixture was concentrated down and purified by preparative TLC to afford B which was coupled with 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-ylboronic acid using methods disclosed above to give 2-(2-(trifluoromethoxy)-5-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)-1,3,4-oxadiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1C(=O)O
Reaction time: 8 h

Procedure:
10% (wt.) Pd on activated carbon (0.05 equiv) was added to a flask charged with 2-nitrobenzoic acid (35) (1.0 equiv) under a N2 atmosphere. To the flask was added MeOH (0.25 M), and stirred under two H2 balloons overnight. After reaction complete, the flask was flushed with N2 gas, and the reaction mixture was filtered through celite. The volatiles were removed to afford crude 2-amino benzoic acid (36).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:34])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=3)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=2)[N:8]=1)(=[O:3])[CH3:2].[CH2:35](O)[CH2:36][OH:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:32][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH:29]([CH3:30])[CH3:31])[C:21]([NH:20][C@H:16]([CH2:17][CH2:18][OH:19])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([C:1]3([CH3:2])[O:37][CH2:36][CH2:35][O:3]3)[N:5]([CH3:34])[CH:6]=2)=[CH:10][CH:11]=1)=[O:33]
Reactant: OCCO
Reactant: CC(=O)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn(C)c(C4(C)OCCO4)n3)cc2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 15.6 %

Procedure:
150 mg (0.31 mmol) of (S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide in 2 mL of benzene was treated with 34.6 uL (0.62 mmol) of ethane-1,2-diol and 59 mg (0.31 mmol) of p-toluenesulfonic acid monohydrate. The reaction was stirred at 70° C. for 2 h after which the solvents were evaporated and the residue purified via reverse phase HPLC (acetonitrile/water). 25.5 mg (16% yield) of 4 was obtained and characterized by LCMS and HNMR.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:34]=[CH:33][C:22]([CH2:23][NH:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]([CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:17][CH:16]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(Cc1ccc(Br)cc1)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-((tert-butoxycarbonyl)amino)benzoic acid (2.0 g, 8.43 mmol), tert-butyl 2-((4-bromobenzyl)amino)acetate INT-60 (2.53 g, 8.43 mmol) and TEA (1.76 mL, 12.6 mmol) in DMF (15 mL) was added HATU (3.53 g, 9.27 mmol) at room temperature. After stirring at room temperature for 2 h the reaction mixture was diluted with EA (150 mL) and washed with brine (200 mL). The organics were concentrated in vacuo and the residue was purified by chromatography (EA/hexanes) to afford 3.97 g (91%) of tert-butyl 2-(N-(4-bromobenzyl)-4-((tert-butoxycarbonyl)amino)benzamido)acetate INT-61 as a viscous oil. LCMS-ESI (m/z) calculated for C25H31BrN2O5: 519; found: 517/519 [M−H]−, tR=2.68 min (Method 10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:6]=[CH:7][C:8]=1[CH:9]=[O:10].S(=O)(=O)([OH:23])N.Cl([O-])=O.[Na+].CCCCCC>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:6]=[CH:7][C:8]=1[C:9]([OH:23])=[O:10]
Reactant: NS(=O)(=O)O
Reactant: COc1cc(-c2ccccc2C(F)(F)F)ccc1C=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1cc(-c2ccccc2C(F)(F)F)ccc1C(=O)O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
The 3-methoxy2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde of Step B (0.95 g, 3.41 mmol) and sulfamic acid (0.43 g, 4.43 mmol) were dissolved in a mixture of tetrahydrofuran and water (1:1, v/v, 30 mL). Sodium chlorite (0.31 g, 4.43 mmol) was added under stirring, and the solution turned yellow. After 30 minutes, additional sodium chlorite and sulfamic acid were added, and the solution stirred an additional hour. The solution was then concentrated, and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried and concentrated to yield an oil, which solidified upon trituration with hexane to provide the title compound (0.84 g) as a yellow solid, which was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]1[C:53]2[C:54]([O:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=3)=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][O:50]1>CN(C)C=O>[CH3:48][CH:49]1[C:53]2[C:54]([O:58][C:59]3[N:64]=[CH:63][C:62]([NH:65][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:61][CH:60]=3)=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][O:50]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1OCc2cccc(Oc3ccc(N)cn3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2C(C)OC3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 8 ml vial (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (32.2 mg, 0.158 mmol) was dissolved in N,N-dimethylformamide (0.5 ml) to give a colourless solution. DIPEA (0.035 ml, 0.198 mmol) and HATU (60.3 mg, 0.158 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. 6-[(3-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinamine (Intermediate 100, 32 mg) was dissolved in 1.5 ml of DMF and the obtained solution was added to the reaction mixture. It was shaken at 60° C. After 2 hours, no reaction occurred. Additional 0.5 ml of a solution [obtained dissolving in 0.5 ml of DMF (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (32.2 mg, 0.158 mmol), DIPEA (0.035 mL, 0.198 mmol) and HATU (60.3 mg, 0.158 mmol)] was added to the reaction mixture. It was shaken at 60° C. over weekend. After that time, only traces of the title compound along with the Intermediate 100 was detected. The reaction mixture was evaporated under vacuum using the Vaportec V10 to give the crude product which was purified by silica gel chromatography (Biotage SP1 system, 10 g-SNAP Silica column) with Cyclohexane/EtOAc as eluents (from 3/1 to 1/1 in 10 CV; then 1/1 for 10 CV). The collected fractions afforded 4.9 mg of the title compound mixed with the amino acid and 61 mg of a mixture of starting material (Intermediate 100) and the amino acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14]CC(S(N)(=O)=O)C)=[CH:8][CH:7]=2)=[CH:2]1.C([N:24]([CH2:27]C)CC)C.[CH3:29][N:30](C)[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][N:24]([CH3:27])[S:31]([NH:30][CH3:29])(=[O:33])=[O:32])=[CH:10][CH:11]=2)=[CH:2]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(CCCCc1ccc(-c2ccsc2)cc1)S(N)(=O)=O
Solvent: ClCCl
Product: CNS(=O)(=O)N(C)CCCc1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
A solution of 0.5 g (1.5 mmol) of material from Example 28, Step B and 0.52 mL (3.70 mmol) of triethylamine in 10 mL of dichloromethane was cooled to 0° C. A solution of 0.16 mL (1.5 mmol) of dimethylsulfamoyl chloride in 1 mL of dichloro-methane was added dropwise. The ice-bath was removed and the mixture was stirred at ambient temperature for 5 h. The mixture was washed with 10 mL of 10% aqueous sodium bisulfate, the organic layer was separated and the aqueous layer extracted three times with 5 mL of dichloromethane. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in 50% ether/hexane and filtered to afford 0.22 g (46%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[ClH:13].Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>C(O)C>[ClH:13].[NH:15]1[CH2:16][CH:17]=[C:18]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 7.7 g of 5-nitro-1H-indole and 225 ml of ethanol saturated with hydrogen chloride and 22.5 g of the hydrate of 4-piperidone hydrochloride was refluxed for 3 hours under a nitrogen atmosphere and the mixture was then stirred at room temperature for one hour and at 0° C. for another hour. The mixture was filtered and the recovered product was rinsed with iced ethanol, with ethyl acetate and ether to obtain 14 g of raw product. The latter was crystallized from 600 ml of 1-1 methanol-water mixture and after standing overnight at 0° to 5° C., the mixture was filtered. The product was rinsed with methanol and dried to obtain 9.8 g of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole hydrochloride melting at 275° C.