Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N:21]2[C:25]([NH2:26])=[CH:24][C:23]([CH3:27])=[N:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:26][C:25]3[N:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=4)[N:22]=[C:23]([CH3:27])[CH:24]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: Cc1cc(N)n(-c2cccc(Cl)c2)n1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2cnn3ccc(Cl)nc23)n(-c2cccc(Cl)c2)n1
Yield: 95.8 %

Procedure:
A solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (150 mg, 0.69 mM, 1.0 equiv), 1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-amine (140 mg, 0.69 mM, 1.0 equiv, available from Enamine, Ltd, Cincinnati, Ohio Cat# EN300-02447), N,N-diisopropylethylamine (0.18 mL, 1.0 mM, 1.0 equiv), and 15 mL of dichloromethane was stirred at ambient temperature for 3 days. The reaction was partitioned between dichloromethane and water. The dichloromethane phase was dried over sodium sulfate and vacuum filtered through silica gel. The silica gel pad was washed with 95:5 dichloromethane:methanol. The combined filtrates were concentrated to give 250 mg (93%) of 5-chloro-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was 74% pure by HPLC and used without further purification. LCMS (ESI) m+H=387.2, (two chlorine isotope pattern).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.C(O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:1][O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[N:12]=[C:13]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: OCCO
Reactant: COC(=O)[C@@H](C)Nc1ncccc1NC(=O)c1ccc(Cl)cc1
Solvent: O
Product: C[C@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 96 %

Procedure:
A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alanine methyl ester (27.4 g, 0.0822 mole) in ethylene glycol (150 ml) was refluxed under nitrogen for 1.75 hours and then cooled. One-third of this solution was added to water (1 liter), extracted with ethyl acetate twice and the combined organic layers were washed three times with water and once with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered, and evaporated to give 8.3 g of a yellow solid (96% yield). The solid was dissolved in hot isopropyl ether (with a little isopropyl alcohol) and filtered hot. Upon cooling to room temperature, solid precipitated, which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at room temperature to give 3.29 g of title compound, mp 110°-113° C.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12](Cl)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 42.8 %

Procedure:
A mixture of 0.3 g (1.01 mmole) 1-(1,1-dimethylethyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 0.3 g (3.48 mmoles) piperazine in 1 mL pyridine was heated under reflux for 18 hours. After cooling the mixture was concentrated under reduced pressure. The residue was poured in 10 mL of 10% acetic acid. After filtration of little insoluble the solution was taken to pH 6.5, saturated with brine and extracted three times with dichloromethane. After evaporation the resulting solid obtained was purified in water to give 0.15 g of 1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid purified as in method 1.
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].[Br-].[Li+].C(N(CC)CC)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>C(#N)C>[N+:1](=[C:3]([C:17]([O:18][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Into 5 ml of dry acetonitrile were suspended 263 mg (1 millimole) of p-nitrobenzyl 2-diazoacetoacetate and 122 mg (1.4 millimoles) of lithium bromide. To the mixture were added 220 μl (1.6 millimoles) of triethylamine and then 190 μl (1.5 millimoles) of trimethylsilyl chloride while agitating under an argon atmosphere at a room temperature. The resultant was heated up to 40° C. and agitated at the same temperature overnight, followed by concentration under a reduced pressure. To the residue was added 20 ml of dry hexane, and the resultant was agitated for 30 min. at a room temperature. Insoluble materials were removed by filtration and the filtrate was concentrated to dryness under a reduced pressure to give 330 mg (yield 87%) of the desired compound in a yellow solid. The physical properties of the product were in agreement with those of the product obtained in Example 1.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[CH3:22]>>[CH3:22][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:14]=1[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)[CH:18]=[O:19]
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: Cc1cc(C=O)ccc1F
Product: Cc1cc(C=O)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 4 and 4-fluoro-3-methyl-benzaldehyde.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl[CH:27]([O:29]C)Cl>C(Cl)Cl>[CH:27]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[CH2:25][CH:17]([CH2:16][NH:15][S:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[CH2:18]2)=[O:29]
Reactant: COC(Cl)Cl
Reactant: O=S(=O)(NCC1Cc2ccccc2C1)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: -20 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
5.33 g (40.0 mmol) of anhydrous aluminum chloride was suspended in 20 ml of methylenechloride and added with 1.61 g (5.00 mmol) of 2-[(4-chlorophenyl)sulfonylaminomethyl]indan, followed by cooling at -20° C. 10 ml of methylene chloride containing as dissolved 0.68 ml (7.5 mmol) of dichloromethylmethylether was slowly added dropwise thereto, followed by stirring for 1 hour at the same temperature. The reaction solution was poured into ice-water and stirred for 1 hour. Thereafter, the organic phase was collected, washed, dried, and the solvent was removed. The residue was purified by silica gel column chromatography (chloroform), followed by recrystallizing from a solvent mixture of ethylacetate and hexane to obtain 375 mg of colorless crystals. Yield: 22%
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][O:13]C(=O)C)[CH:9]=[CH:8][C:7]=1[Br:17])(=O)C.C(OCC1C=CC=C(COC(=O)C)C=1Br)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[Br:17]
Reactant: CC(=O)OCc1ccc(Br)c(COC(C)=O)c1
Agent: CC(=O)OCc1cccc(COC(C)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1ccc(Br)c(CO)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
An about 93:7 mixture (36.7 g) of 2,4-bis(acetoxymethyl)-bromobenzene and 2,6-bis(acetoxymethyl)bromobenzene was dissolved in methanol (183 ml) and cooled to 10° C. To this solution was added dropwise 10% aqueous sodium hydroxide solution.(133 g). The reaction mixture was stirred at room temperature for 1 hr. and the solvent (about 200 ml) was evaporated. The residue was neutralized with dilute hydrochloric acid (about 200 ml). To the neutralized solution was added toluene (150 ml) and the mixture was stirred at 80-85° C. for 1 hr and cooled. The resulting crystals were collected by filtration and dried under reduced pressure to give an about 93:7 mixture (22.2 g, 83.7%) of 2,4-bis(hydroxymethyl)bromobenzene and 2,6-bis(hydroxymethyl)-bromobenzene as almost white crystals. 2,4-bis(Hydroxymethyl)-bromobenzene was isolated by preparative HPLC and used in the measurement.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]23[CH2:17][CH2:16][C:15](=[O:18])[CH:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14]3)[N:3]=[CH:2]1.[BH4-].[Na+].O>C(O)C>[NH:1]1[CH:5]=[C:4]([C:6]23[CH2:17][CH2:16][CH:15]([OH:18])[CH:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14]3)[N:3]=[CH:2]1
Reactant: O=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Temperature: 37.5 °C
Reaction time: 4 h

Procedure:
To a solution of 8a-(1H-imidazol-4-yl)-1,3a,8,8a-tetrahydro-2H-cyclopenta[a]inden-3-one (1 g) in 40 ml of ethanol was added 0.16 g of sodium borohydride under a nitrogen atmosphere. The reaction mixture was stirred at 35-40° C. for 4 hours and then poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The combined organic layers were dried over sodium sulfate and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using methylene chloride/methanol (95:5) as eluent. The yield was 0.6 g, m.p. 183-186° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:14](O)[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=C[C:21]([S:24](O)(=O)=O)=CC=1.SCO>C(O)(C)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:14]([S:24][CH3:21])[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Agent: OCS
Solvent: CC(C)(C)O
Product: CSC1CN(C)C(=O)N1c1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a three-necked flask provided with a magnetic stirring bar, dry-ice/acetone condenser and a gas inlet tube were charged 70 grams of 3-(5-t-butyl-3-isoxazolyl)-1-methyl-4-hydroxy-2-imidazolidinone, 5.0 grams of p-toluene sulfonic acid and 700 milliliters of t-butanol. A slow stream of gaseous mercaptomethanol was introduced into the stirred reaction mixture, a total 54 grams of mercaptomethanol being added over a 3 hour period. After 17 hours stirring at room temperature. HPLC and TLC analyses indicated unreacted starting material as the major component. Stirring was continued an additional 24 hours after which time HPLC analysis indicated about 50 percent conversion of starting material to desired product. The reaction mixture was then neutralized by the additiono of 10 grams of potassium carbonate in 15 milliliters of water and excess mercaptomethanol was removed by bubbling nitrogen gas through the reaction mixture. Evaporation of solvent, afforded a semi-solid gummy residue. The residue was dissolved in methylene chloride and adsorbed onto 840 grams of silica gel in a two liter sintered glass funnel. The silica gel was eluted with hexane:methylene chloride, methylene chloride and methylene chloride:methanol and the eluent fractions (about 500 milliliters) were analyzed by TLC or HPLC. Combination of appropriate fractions afforded 58 grams of material identified as the desired product.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:6]([F:22])[C:5]=1Cl)(=[O:3])[CH3:2].[N-:24]=[N+]=[N-].[Na+]>CC(C)=O.O>[F:22][C:6]1[C:5]2[C:4](=[C:1]([CH3:2])[O:3][N:24]=2)[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccccc1F
Temperature: 65 °C

Procedure:
To a solution of methyl 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)picolinate (WO 2005/051906) (2 g, 5 mmole) in a mixture of acetone (36 ml) and H2O (12 ml) is added NaN3 (487 mg, 7.5 mmol). The reaction is heated at 65° C. for 16 h and cooled to room temperature. Acetone is concentrated and the resulting mixture is extracted with EtOAc (2×50 ml). The combined organic solution is washed with brine (50 ml), dried over MgSO4 and concentrated to give a yellow solid. To the solid is added H2O (24 ml) and the reaction is heated at reflux for 3 h. The reaction is cooled to room temperature, filtered, and washed with H2O. The resulting solid is dried under high vacuum with P2O5 at 65° C. for 24 h to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH:15]=[C:14]2[C:18]2[CH:23]=[CH:22][C:21]([C@H:24]([O:30]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=2)=[CH:8][CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].C1COCC1.Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH:15]=[C:14]2[C:18]2[CH:19]=[CH:20][C:21]([C@H:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC[C@@H](O)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A mixture of 45 (40 mg, 0.069 mmol), K2CO3 (10 mg, 0.072 mmol) in methanol (0.5 mL) was stirred at room temperature. After 1 h, the diester had not dissolved and so 0.2 mL THF was added. The reaction was stirred further for 1.5 h and then 10 mL 1 M HCl was added. The mixture was extracted with ethyl acetate (2×20 mL) and the combined solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography using a Combiflash unit by Teledyne Isco (12 g silica gel, 0%→20% ethyl acetate/hexanes) gave the title compound (22 mg, 0.051 mmol, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Amino-3-nitrobenzoic acid may be prepared as described in Chapman, E. and Stephen, H., "Preparation of phthalmic acids and their conversion to anthranilic acids," J. Chem. Soc., (1925), 1151. To a mixture of this acid (14.00 g, 76.9 mmol) and cesium carbonate (20.00 g, 61.5 mmol) in dimethylformamide (150 mL) at 0° C. methyl iodide (12.00 g, 84.5 mmol) was added with stirring. After 20 minutes, it was warmed to room temperature and stirred for 3 hours. Most of the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (250 mL) and water (100 mL). The organic layer was separated, the aqueous layer was washed with ethyl acetate (250 mL) and the combined organic extract was dried over magnesium sulfate. After concentrating, the residue was triturated with ether to obtain the first crop of product as a yellow solid (3.20 g). The filtrate solution was concentrated, and the residue was passed through a flash column on silica gel eluting with 4:1 hexane:ethyl acetate to afford a slightly impure product. This material was triturated with methanol to obtain a pure second crop of product (9.10 g); total 12.3 g in 82% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.[CH3:26][O:27][C:28]1C=CC(CN)=[CH:30][CH:29]=1>>[NH2:3][N:4]([CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH2:5][C:6]1[CH:2]=[CH:1][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Product: COc1ccc(CN(N)C=NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The compound of Example 6 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 4-methoxybenzylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 333.41; found mol. wt. (M+H) 334.2; 667.0 (Dimer)
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C.C(OCC)(=O)C>[Br:46][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)Cc1cc(-c2ccc(CO)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(-c2ccc(CBr)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
3-(4-Hydroxymethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (280 mg, 0.734 mmol, see step (a) above) was dissolved in DMF (10 mL). PPh3 (459.2 mg, 1.75 mmol) and CBr4 (580.3, 1.75 mmol) were added to the resultant solution. The mixture was stirred for 24 h at room temperature and then diluted with ethyl acetate. The organic phase was washed with water (50 mL) and brine (50 mL) and then dried over MgSO4. After removing the solvents, the residue was purified by column chromatography using hexane:acetone (5:1) as eluent to give the sub-title compound (314.9 mg, 0.709 mmol, 76% yield).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36]([C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)=[O:37])[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCCI)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Yield: 79.8 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.353 g, 0.826 mmol), 4-iodo-4′-fluorobutyrophenone (0.27 g, 0.826 mmol), and potassium carbonate (0.17 g, 1.24 mmol) in N,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.39 g, 80%); MS for C35H46FN3O4 m/z 592 (M+H)+.
Reaction SMILES: [CH:1]1([C:14]([OH:16])=[O:15])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+].O.O1CCOCC1>[CH2:21]([O:20][C:18]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:1]1[C:14]([OH:16])=[O:15])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1NCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution, cooled in ice, of 3.0 g of 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxylic acid in 7 ml of 2M sodium hydroxide solution, 17 ml of water and 17 ml of dioxan were added in alternating portions 12.5 ml of 2M sodium hydroxide solution and a solution of 3.6 ml of benzyl chloroformate in 9 ml of dioxan. After completion of the additions the mixture was stirred at room temperature overnight and the dioxan-was then removed by evaporation under reduced pressure. The solution obtained was diluted with water, washed twice with diethyl ether, acidified with 25 ml of 1M sulphuric acid and extracted three times with ethyl acetate. The organic extracts were combined, washed twice with water, dried over anhydrous magnesium sulphate and evaporated to give 4.54 g of 2-benzyloxycarbonyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxylic acid, MS: m/e 351 [M+H]+, which was used without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH2:22][N:30]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:27])=[O:28]
Reactant: C1CCCNCC1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCCCC5)c4)cc23)CCS1(=O)=O
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 25.1 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.093 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and acetic acid (0.056 mg, 0.929 μmol) was added, hexahydro-1H-azepine (0.453 mL, 4.02 mmol) was added. The mixture was left stirring 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (399 mg, 0.929 mmol). The vial was sealed and the mixture heated in a microwave 10 minutes at 100° C. The sodium triacetoxyborohydride polymer bound was removed by filtration, and the mixture was run through prep HPLC from 10% acetonitrile containing 0.1% TFA to 50% acetonitrile containing 0.1% TFA in 25 minutes. The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[C:16](Cl)(=O)C>CO>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([O:11][C:12]([F:14])([F:13])[F:15])[CH:4]=1
Reactant: O=C(O)c1ccc(F)c(OC(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)c(OC(F)(F)F)c1
Yield: 75 %

Procedure:
To a stirred suspension of 21.2 g (96.9 mmol) 4-Fluoro-3-trifluoromethoxy-benzoic acid (JRD-Fluoro) and 161 ml methanol were added 30.4 g (387.6 mmol) acetyl chloride drop wisely at 0° C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane:ethylacetate). The desired product 14a was obtained in 75% yield (17.3 g; 72.7 mmol)