Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][N:17]1[C@@H:22]([CH3:23])[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]1[CH3:31]>CO>[NH2:6][CH2:15][CH2:16][N:17]1[C@@H:22]([CH3:23])[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]1[CH3:31]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
Hydrazine hydrate (0.11 ml) was added to a solution of tert-butyl(cis)-4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3,5-dimethyl-1-piperazinecarboxylate (0.736 g) [see Preparation 6] in methanol (1.1 ml). The reaction mixture was then stirred at 50° C. for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 10% citric acid. The aqueous layer was separated, basified with potassium carbonate, and the product extracted with tetrahydrofuran: ethyl acetate, 1:1, several times. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl(cis)-4-(2-aminoethyl)-3,5-dimethyl-1-piperazinecarboxylate (0.33 g) as a oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([OH:34])=O)(=[O:30])=[O:29])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[O:34])(=[O:29])=[O:30])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: C1COCCN1
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)O)s2)cc1C#N
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: ClCCl
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)N3CCOCC3)s2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Prepared using General Procedure 16: To (R)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 158 (15 mg, 0.03 mmol) in DCM (0.4 mL) was added HATU (26 mg, 0.07 mmol) and DIEA (7.8 mg, 0.06 mmol). After 30 min, morpholine (52 mg, 0.6 mmol) was added and the reaction stirred for 18 h at room temperature. The reaction was quenched with water (100 μL) and the solvent evaporated. The crude material was purified by preparative HPLC to afford 8 mg (47%) of (R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-morpholino-2-oxoethanesulfonamide 162. LCMS-ESI (m/z) calculated for C28H30N4O5S2: 566.1; found 567.2 [M+H]+, tR=3.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.I[C:26]1[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:30][CH:31]=1.N>>[F:33][C:32]([F:35])([F:34])[C:28]1[CH:27]=[C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)[CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(C(F)(F)F)c3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-3(2H)-pyridazinone and substituting 3-iodobenzotrifluoride in place of 4-bromothioanisole (yield: 210 mg, 59.5%). mp 103-105° C. 1H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H), 7.18 (d, J=9 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.65 (m, 2H), 7.95 (m, 3H), 8.04 (m, 2H). MS (DCI/NH3) m/z 505 (M+H)+, 525 (M+NH4)+. Anal. calc. for C24H16ClF3N2O3S: C, 57.14; H, 5.56. Found: C, 56.61; H, 3.28; N, 5.38.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]=[N:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[N+:25]([O-])=O)[C:12]([OH:28])=[C:11]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.Cl>C(O)C.[Zn]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[N:16]=[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]3=[N:25]2)[C:12]([OH:28])=[C:11]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N=Nc2cc(OCc3ccccc3)cc(C(C)(C)C)c2O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Zn]
Solvent: CCO
Product: COc1ccc2nn(-c3cc(OCc4ccccc4)cc(C(C)(C)C)c3O)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.4 %

Procedure:
To a stirred solution of XII (3.12 Kg) in ethanol (36 L), a glucose solution (2.496 Kg in 15.6 L 2N NaOH) was added dropwise under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hr. Zinc powder (5.46 Kg) previously activated with HCl solution was charged portionwise to the reaction mixture. The reaction mixture was heated at 60° C. for 4 hr to 6 hr until N-Oxide completely consumed. The reaction mixture was cooled and extracted with 15 liters of a 2:1 hexane:toluene mixture. The organic layer was separated and the aq. layer was re-extracted with a 2:1 hexane:toluene mixture (15 L×3). The organic layer was combined and evaporated up to 90% volume. Upon standing at room temperature the organic layer was solidified. The solid was purified by the slurry wash with 5 L of a 95:5 hexane:toluene mixture followed by a methanol slurry wash (3 L) to give title compound (XIII) (1.34 Kg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:22])[CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=O.C1COCC1>>[CH3:22][N:4]([CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:3][CH2:2][OH:1]
Reactant: CN(CCO)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Solvent: C1CCOC1
Product: CN(CCO)CCCN1CCCc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C

Procedure:
1-(3-((2-Hydroxyethyl)(methyl)amino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (200 mg, 0.651 mmol) was stirred in borane-tetrahydrofuran complex, 1M sol'n in THF (6.507 mL, 6.51 mmol) until the material dissolved. The resulting solution was then heated at 60° C. overnight. The reaction mixture was then cooled in an ice bath and quenched with methanol (slowly). The solution was then concentrated, redissolved in methanol (5 mL) and stirred with 1M HCl (5 mL) at reflux for 1 h. The mixture was then basified with 1M NaOH and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel eluting with ethyl acetate, followed by 5% (2M NH3/methanol) in dichloromethane. 1H NMR (DMSO-d6) δ 7.88 (dd, J=9.3, 2.7 Hz, 1H), 7.77 (d, J=2.7 Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 4.40 (t, J=5.4 Hz, 1H), 3.51-3.32 (m, 6H), 2.74 (t, J=6 Hz, 2H), 2.41-2.33 (m, 4H), 1.89-1.81 (m, 2H), 1.72-1.64 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:32])=[C:5]([F:31])[CH:6]=[C:7]2[C:12]=1[N:11]([C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH:22]([CH3:24])[CH3:23])[N:14]=1)[CH:10]=[C:9]([C:25]([O:27]CC)=[O:26])[C:8]2=[O:30]>C(O)(=O)C>[Cl:2][C:3]1[C:4]([F:32])=[C:5]([F:31])[CH:6]=[C:7]2[C:12]=1[N:11]([C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH:22]([CH3:24])[CH3:23])[N:14]=1)[CH:10]=[C:9]([C:25]([OH:27])=[O:26])[C:8]2=[O:30]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Yield: 94.1 %

Procedure:
To 3 ml of the mixed solution of 4N hydrochloric acid and acetic acid (1:1, v/v) was added 300 mg of ethyl 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 19 hours with stirring. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 265 mg of the title compound as a yellow powder.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([S:13]([NH:16][C:17](=[O:30])[NH:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([CH3:29])[N:20]=2)(=[O:15])=[O:14])=[CH:10][C:11]=1[CH3:12])(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([S:13]([NH:16][C:17](=[O:30])[NH:18][C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([CH3:29])[N:20]=2)(=[O:15])=[O:14])=[CH:10][C:11]=1[CH3:12]
Reactant: CC(=O)OCCc1sc(S(=O)(=O)NC(=O)Nc2cc(C(F)(F)F)cc(C)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(F)(F)F)cc(NC(=O)NS(=O)(=O)c2cc(C)c(CCO)s2)n1
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a solution of 0.25 g 2-{3-methyl-5-[({[6-methyl-4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)sulfonyl]-2-thienyl}ethyl acetate in 5 ml methanol was added 0.01 ml 28% aqueous sodium hydroxide and the mixture was kept at room temperature for 3 h. The reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine and evaporated. The residue was triturated with t-butylmethyl ether/heptane to yield 0.177 g of the title compound as off white powder MS (ISN) M−H+=422.4.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[S:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl.C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[S:9](=[O:33])[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc(O)cc1)c1sc2ccccc2c1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(C1=C(c2ccccc2)c2ccccc2S1=O)c1ccc(O)cc1
Reaction time: 72 h

Procedure:
The product from Example 3 (5.0 g.; 0.0151 mole) and 2.8 g. of m-chloroperbenzoic acid were dissolved together in chloroform. The mixture was allowed to stand at room temperature for about 3 days. The solution then was washed twice with aqueous sodium bicarbonate solution, then with water, and was dried over magnesium sulfate. The solution then was concentrated to dryness. Thin-layer chromatography (TLC) run on the crude product revealed the presence of the starting material, some sulfone, and the desired product. The mixture was slurried in hot benzene, allowed to cool, and filtered to obtain 2.6 g. of a material having m.p. 140°-145° C. TLC on this product indicated some sulfone was still present. The solid was slurried in benzene, warmed, and filtered while hot. The collected solid then was slurried in benzene containing a small amount of ethanol, heated, and allowed to cool. The title compound (1.3 g.) crystallized out and was collected by filtration. TLC of this product indicated the presence only of traces of the sulfone contaminant. The melting point of the product was 215° C. The product was dried in vacuo at 120° C. overnight to further remove any solvent which might be present.
Reaction SMILES: [Cl-].[Na+].[Ca:3].[Mg:4].[C:5](=[O:8])([O-:7])[O-:6].[Na+].[Na+].[OH-:11].[Ca+2].[OH-].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[Na+].[Na+]>[Cl-].[Na+].O>[C:5](=[O:6])([O-:8])[O-:7].[Ca+2:3].[OH-:15].[Mg+2:4].[OH-:11].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[Ca+2:3]
Reactant: [Ca]
Reactant: [Mg]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: [Mg+2]

Procedure:
A process for the preparation of sodium chloride from crude brine containing calcium ions and magnesium ions which comprises adding sodium carbonate, calcium hydroxide and sodium sulphate to said brine to form calcium carbonate, magnesium hydroxide and calcium sulfate as insoluble compounds; separating said insoluble compounds from the crude brine to obtain a purified brine; evaporating water from the purified brine and separating the sodium chloride crystallized in the process leaving a mother liquor; and, crystallizing and separating sodium sulfate from the mother liquor and returning the sodium sulfate to the crude brine to be purified.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>CC#N>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]2[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=3[NH:1][C:23]2=[O:25])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc([N+](=O)[O-])c2N)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3c([N+](=O)[O-])cccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(2-amino-3-nitrophenyl)-4-methylbenzenesulfonamide from Step A (2.00 g, 6.51 mmol) in CH3CN (100 mL) was added triphosgene (966 mg, 3.25 mmol) and the mixture was stirred at ambient temperature for 30 min. The precipitate was isolated by filtration and dried in vacuo to give the title compound. MS: m/z=334 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH2:3][CH2:2]1.[S:14]1[CH2:20][C:18](=[O:19])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[S:16].[Cl-].[NH4+].N>C(O)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18]3=[O:19])[N:11]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(N2CCOCC2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(N3CCOCC3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 1.65 g of 2-morpholinothiazole-4-carbaldehyde, 1.3 g of rhodanine-3-acetic acid, 1g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 35 ml of ethanol, giving the title compound as yellow needles.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([Cl:16])[CH:5]=[CH:4][N:3]=1.CC1C=CN=C(C=C)C=1[CH2:26][O:27]C1CCCCO1.CC1C=CN=C(CO)C=1COC1CCCCO1>[Pd]>[Cl:16][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:26][OH:27])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: C=Cc1nccc(C)c1COC1CCCCO1
Reactant: Clc1ccnc(Cl)c1COC1CCCCO1
Agent: [Pd]
Agent: Cc1ccnc(CO)c1COC1CCCCO1
Product: OCc1nccc(Cl)c1COC1CCCCO1

Procedure:
Pd catalyzed vinylation of 2,4-dichloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (1.71 g. 6.52 mmol) according to the synthesis of 4-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine subsequent ozonolysis and reduction according to the synthesis of [4-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol and flash chromatographic purification yielded the title compound. MS (m/z): 257.8 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:46])[CH2:20][CH2:21][C:22]2[N:23]=[N:24][N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:26]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].Cl.C(O)(C)C.C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:46])[CH2:20][CH2:21][C:22]2[N:26]=[N:25][NH:24][N:23]=2)=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CCc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C)c1
Agent: Cl
Solvent: CC(C)O
Solvent: O=CO
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CCc3nn[nH]n3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-(2,4-dimethylphenyl)-4-(1-hydroxy-3-(2-trityl-2H-tetrazol-5-yl)propyl)-N-isobutylbenzenesulfonamide (20 mg, 0.029 mmol), at room temperature was treated with a solution of HCl (6N in isopropanol, 2 mL, 12.00 mmol) and isopropanol (2 mL). The reaction mixture was stirred at 20° C. for 2 hours, then the solvent evaporated in vacuo and the crude partitioned between ethyl acetate (5 mL) and water (5 mL). The organic phase was separated by hydrophilic frit then evaporated in vacuo to give a residue. LCMS analysis showed the reaction was incomplete, so the residue was re-dissolved in dichloromethane (DCM) (2 mL) and treated with formic acid (0.5 mL, 13.04 mmol). The solution was left to stand for 2 hours. The solvent was evaporated in vacuo then dissolved in a 1:1 mixture of MeOH and DMSO and purified by MDAP (Method F) to give the required product, 3.69 mg. LCMS (M+1) 444, RT 1.09 mins.
Reaction SMILES: C(OC)(=O)C#C.[Br:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([NH2:19])=[O:18])=[C:13]2[C:9]=1[C:10]([CH2:20]N(C)C)=[CH:11][NH:12]2.[N+:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([O-:26])=[O:25]>ClCCl.C(#N)C>[Br:7][C:8]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[NH2:19])=[C:13]2[C:9]=1[C:10]([CH2:20][CH:27]([N+:24]([O-:26])=[O:25])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:11][NH:12]2
Reactant: CN(C)Cc1c[nH]c2c(C(N)=O)ccc(Br)c12
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C#CC(=O)OC
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c[nH]c2c(C(N)=O)ccc(Br)c12)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Methyl propiolate (2.300 mL, 27.5 mmol) was added slowly to a suspension of crude 4-bromo-3-((dimethylamino)methyl)-1H-indole-7-carboxamide (6.27 g, 21.17 mmol) and ethyl 2-nitroacetate (3.66 g, 27.5 mmol) in dichloromethane (151 mL) and acetonitrile (151 mL). After 30 min, the mixture was concentrated and partitioned between EtOAc and 1 M aqueous HCl. The organic phase was washed with NaHCO3 (aq) and brine, dried and concentrated. The residue was coated subjected to column chromatography on silica gel (80 g), eluting with EtOAc-hexane (gradient from 50:50 to 80:20) to provide the desired product as a solid (4.60 g, 57% yield). LCMS (M+H)+ m/z 383.8, 385.8.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18]>[Ni].CO>[CH3:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][NH2:18]
Reactant: Cc1c(C#N)ccc2c1ncn2C1CCCCO1
Agent: [Ni]
Solvent: CO
Product: Cc1c(CN)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
A mixture of 162 (9.8 g, 52.5 mmol), MeOH(NH3 in MeOH) and Raney-Ni (>15 eq) was stirred under hydrogen at 25° C. for 2 h. The mixture was filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0% to 10% MeOH) to afford 7.0 g (70%) of (4-methyl-1-tetrahydropyran-2-yl-benzimidazol-5-yl)methanamine (164) as yellowish oil: LC/MS: m/z=246 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([I:17])=[C:6]2[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].C(O)C.[CH:32]([O:35][C:36](Cl)=[O:37])([CH3:34])[CH3:33]>O.C(Cl)Cl.[Fe].N1C=CC=CC=1>[CH:32]([O:35][C:36](=[O:37])[NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:13]3[C:8]([C:7]=2[I:17])=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)=[CH:19][CH:20]=1)([CH3:34])[CH3:33]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc2c(I)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOc1ccc2c(I)c(-c3ccc(NC(=O)OC(C)C)cc3)n(CC3CC3)c2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
A mixture of 1-Cyclopropylmethyl-6-ethoxy-3-iodo-2-(4-nitro-phenyl)-1H-indole (990 mg, 2.14 mmol), iron powder (690 mg, 11.8 mmol), NH4Cl (690 mg, 12.9 mmol), ethanol (22 mL), and H2O (8 mL) were heated at 80° C. for 90 minutes. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The organic layer was dried, concentrated and purified by silica gel chromatography (CH2Cl2). Product containing fractions were used immediately in the next reaction. The compound in CH2Cl2 (80 mL) was treated with pyridine (15 mL) and isopropylchloroformate (1M in toluene, 2.5 mL, 2.5 mmol) and stirred at room temperature for 15 minutes. The reaction mixture was concentrated and extracted with a mixture of EtOAc and aq. HCl. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2Cl2/hexane, 1:1 to 3:1) to provide [4-(1-cyclopropylmethyl-6-ethoxy-3-iodo-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (644 mg, 58%) as a white solid.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][S:17]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:19])=[O:18]
Reactant: OCCCCCCCOc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCOc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A solution of 7-(phenyloxy)-1-heptanol (0.21 g, 1.01 mmol) in anhydrous methylene chloride (20 mL), taken in a 50 mL round bottomed flask was cooled to 0° C. using an ice bath. Methanesulfonyl chloride (0.177 g, 1.55 mmol) was added to this followed by a dropwise addition of triethylamine (0.28 mL, 2.11 mmol). The reaction mixture was then stirred at 0° C. for 1 hour and allowed to attain room temperature in 2 hours. It was then quenched with 1N. HCl (10 mL) and diluted with methylene chloride (20 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2×10 mL). The combined organic layer was washed with 1N. HCl (3×10 mL), water (2×10 mL) and brine (2×mL). The organic layer was dried over Na2SO4. Removal of solvent from the dried extract under reduced pressure afforded the product 7-(phenyloxy)-1-heptyl methanesulfonate (0.25 g, 86.5%). The product from the step B was analyzed yielding the following confirmatory data: 1H-NMR (CDCl3) 1.31-1.52 (m, 6H), 1.71-1.84 (m, 4H), 2.98 (s, 3H), 3.94 (t, 2H, J=6.43 Hz), 4.21 (t, 2H, J=6.51 Hz), 6.80-6.94 (m, 3H) and 7.24-7.30 (m, 2H); 13C-NMR (CDCl3) 25.2, 25.7, 28.6, 28.9, 29.0, 37.1, 67.5, 69.9, 114.3, 120.3, 129.2 and 158.9; IR (neat): 1349 cm−1; MS (ES+): 287 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([I:14])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:15](#[N:19])[CH2:16][C:17]#[N:18].N1CCCCC1.C(O)(=O)C>O.C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([I:14])[C:12]=1[OH:13])[CH:8]=[C:16]([C:15]#[N:19])[C:17]#[N:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(I)c1O
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C(C#N)C#N)cc(I)c1O
Reaction time: 2 h
Yield: 84.3 %

Procedure:
3-tert-butyl-4-hydroxy-5-iodobenzaldehyde (24.8 gm), malononitrile (6.2 gm), piperidine (1.0 ml), acetic acid (3.3 ml) and benzene (300 ml) were refluxed under a Dean and Stark water separator for 2 hours. On cooling a crystalline precipitate formed and was filtered off. Recrystallisation from ethylene dichloride gave pale yellow needles of 3-tert-butyl-4-hydroxy-5-iodobenzylidenemalononitrile (24.2 gm) m.p. 188°.