Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.Cl.[CH:17]1([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:19][CH2:18]1.[OH-].[Na+]>C(OCC)(=O)C>[CH:17]1([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[N:27]2[CH2:32][CH2:31][N:30]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([I:6])=[CH:8][CH:9]=3)=[O:12])[CH2:29][CH2:28]2)[CH2:18][CH2:19]1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), bis(tricyclohexylphosphine)palladium (II) dichloride (132 mg), tripotassium phosphate (3.8 g) and cyclopropylboronic acid (688 mg) were added toluene (10 mL) and water (500 μL) and the mixture was refluxed for 5 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g). 4-(2-Cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g) was dissolved in chloroform (1 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg). To tetrahydrofuran (2 mL) were added 4-iodobenzoyl chloride (169 mg), 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg) and 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (280 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:27][C:28]#[CH:29].CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH2:29][C:28]#[CH:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(C)cc2)cc1OC
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC=C(C(=O)NCCc1ccc(OC)c(OC)c1)c1ccc(C)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
Five hundred miligrams (500 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide (1.47 mmol), 0.11 g (1.47 mmol) of 3-chloropropyne and 5 ml of anhydrous N,N-dimethylformamide were mixed and 64 mg (1.61 mmol) of 60% sodium hydride was added thereto at 0-5° C. The mixture was stirred at 0-10° C. for 30 minutes and then stirred at room temperature. Water was added to the reaction mixture, followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=1:1) to give 180 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(2-propynyloxy)-2-(4-methylphenyl)acrylamide (the present compound 1182).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1C[CH2:34][CH2:33][CH2:32]1.ICCC>CN(C=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH:16]([CH2:32][CH2:33][CH3:34])[C:17]([O:19][CH3:20])=[O:18]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2c3ccccc3nn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2c3ccccc3nn2c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
To a solution of methyl 2-(4-chloro-2-methylpyrimido[1,2-b]indazol-3-yl)acetate (0.289 g; 1 mmol) in dry DMF (4 mL) at −10° C. was slowly added a 1N solution of LHMDS in tetrahydrofuran (1.1 mL; 1.1 mmol). Then, 1-iodopropane (0.146 mL; 1.5 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in dichloromethane furnished 0.252 g (76%) of methyl 2-(4-chloro-2-methylpyrimido[1,2-b]indazol-3-yl)pentanoate as an oil. ESI/APCI(+): 332-334 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:13]Br.O>C(O)(=O)C>[Br:13][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(C=O)cc1OC
Reaction time: 8 h

Procedure:
3,4-Dimethoxybenzaldehyde (398.8 g) is dissolved in acetic acid (1.8 liter), and thereto is added dropwise bromine (136 ml) at room temperature over a period of four hours. The mixture is stirred overnight, and thereto is added dropwise slowly again bromine (60 ml), and the mixture is stirred overnight. The reaction solution is added to water (7 liters), and the precipitated crystals are collected by filtration, washed with water, and dissolved in chloroform (2 liters). The chloroform solution is washed, dried, concentrated, and the residue is crystallized from diisopropyl ether to give 6-bromo-3,4-dimethoxybenzaldehyde (470 g) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5](N)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][S:12]SC.N(OCCC(C)C)=O>>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([S:12][CH3:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)c(F)cc1N
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1cc(F)c(Br)cc1C
Temperature: 75 °C
Yield: 84.9 %

Procedure:
4-Bromo-5-fluoro-2-methylaniline (5 g, 24.5 mmol) was dissolved in 1,2-dimethyldisulfane (35 mL, 394 mmol) and heated to 75° C. under nitrogen. Isoamyl nitrite (8.52 mL, 63.7 mmol) was added dropwise to the reaction via an addition funnel through a reflux condenser (˜1 drop/sec). (NOTE—a large exotherm may occur if addition is too fast.) After addition was complete, the reaction was heated to 95° C. for 1 hour and allowed to cool to ambient temperature. The reaction was concentrated and purified over silica gel (100% hexanes) to afford (4-bromo-5-fluoro-2-methylphenyl)(methyl)sulfane (4.9 g, 20.8 mmol, 85.0% yield) as an orange solid.
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)[C:2]#N.[CH:9]1(CBr)[CH2:11][CH2:10]1.[OH-].[K+]>CO>[CH:9]1([CH2:2][S:1][C:4]2[NH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][CH2:10]1
Reactant: N#CSc1ccc[nH]1
Reactant: BrCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1c[nH]c(SCC2CC2)c1
Reaction time: 1.5 h

Procedure:
A solution of 2-thiocyanopyrrole (12.4 g., 0.1 mole) and cyclopropylmethyl bromide (14.85 g., 0.11 mole) in methanol (500 ml.) was cooled below 0° (ice-salt bath), and stirred vigorously under nitrogen while a solution of potassium hydroxide (12.3 g., 0.22 mole) in 1:1 (by volume) aqueous methanol (400 ml.) was added dropwise during 0.75 hours. The cooling bath was removed and stirring continued for 1.5 hours before neutralization of the excess alkali with solid carbon dioxide. The reaction mixture was poured into 20% brine (500 ml.) and extracted with methylene chloride (3×100 ml.). The combined organic extracts were dried (Na2SO4 +K2CO3), then evaporated in vacuo to provide a red oil (12.1 g.). Distillation of this crude oil afforded 2-cyclopropylmethylthio-pyrrole as a colorless oil (5.8 g. 38%), B.P. 138°-141° at 11 mm. (B) The product from Part A was reacted with ethyl oxalyl chloride as described in Example 39, Part B. Chromatography on silica followed by recrystallization from petroleum ether (B.P. 40°-60°) and hexane gave 5-cyclopropylmethylthio-2-pyrrolylglyoxylic acid ethyl ester as a yellow solid, M.P. 46°. Found: C, 56.81; H, 6.23; N, 5.38. C12H15NO3S requires: C, 56.89; H, 5.97; N, 5.53%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][CH2:16][NH:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:21]
Reactant: CCOC(CCN)OCC
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CCNc1c([N+](=O)[O-])cnc2ccccc12)OCC
Yield: 98.4 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (20.3 g, 97.1 mmol), 1-amino-3,3-diethoxypropane (25.0 g, 116 mmol) and triethylamine (33.8 g, 333 mmol) in dichloromethane for 15 hours to provide (3,3-diethoxypropyl)-(3-nitroquinolin-4-yl)amine (30.5 g) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]([NH:21][C@@H:22]([CH2:28][OH:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCCC1>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:10]([C:19]1[O:29][CH2:28][C@@H:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H](CO)NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Yield: 78.4 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-({[(1 S)-2-ethoxy-1-(hydroxymethyl)-2-oxoethyl]amino}carbonyl)hexanoate (Preparation 60) (4.14 g, 10 mmol) in anhydrous tetrahydrofuran (40 ml) was treated with (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt [Burgess Reagent] (2.62 g, 11 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 1 hour. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (80:20) to (50:50) to afford the title compound as a colourless oil (3.10 g)
Reaction SMILES: CN(C)CCN[C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:30])[C:14]3[N:15]([CH3:29])[C:16]4[CH:17]=[CH:18][C:19]([OH:28])=[C:20]([CH2:25][CH:26]=[CH2:27])[C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].[CH2:32]([O:34]C(C1C2C(=C(C)C3N(C)C4C=CC(OCC=C)=CC=4C=3C=2)C=CN=1)=O)[CH3:33]>ClC1C=CC=CC=1Cl>[CH2:32]([O:34][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:30])[C:14]3[N:15]([CH3:29])[C:16]4[CH:17]=[CH:18][C:19]([OH:28])=[C:20]([CH2:25][CH:26]=[CH2:27])[C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])[CH3:33]
Reactant: C=CCc1c(O)ccc2c1c1cc3c(C(=O)NCCN(C)C)nccc3c(C)c1n2C
Reactant: C=CCOc1ccc2c(c1)c1cc3c(C(=O)OCC)nccc3c(C)c1n2C
Solvent: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2c1c1cc3c(C(=O)OCC)nccc3c(C)c1n2C
Yield: 75 %

Procedure:
1-[(2-Dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-hydroxy-10-allyl-6H-pyrido[4,3-b]carbazole ##STR25## 2 g of 1-ethoxycarbonyl-5,6-dimethyl-9-allyloxy-6H-pyrido[4,3-b]carbazole are dissolved in 80 ml of 1,2-dichlorobenzene, and the solution is refluxed for 10 hours. The mixture is cooled and precipitation is observed. The precipitate is suction-filtered and chromatographed on silica using as eluant first dichloromethane and then a dichloromethane/ethanol mixture. 1.27 g of 1-ethoxycarbonyl-5,6-dimethyl-9-hydroxy-10-allyl-6H-pyrido[4,3-b]carbazole are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:21][C:22](=[NH:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:32])(=[O:31])[NH2:30])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]4[O:19][N:33]=[C:22]([C:23]5[CH:24]=[C:25]([S:29]([NH2:30])(=[O:31])=[O:32])[CH:26]=[CH:27][CH:28]=5)[N:21]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4ccc(-c5ccc(Cl)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.22) (137 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (dichloromethane/MeOH) and crystallization (dichloromethane) as an off-white solid (86 mg, 38%). MS (ISN) 451.2 [(M−H)−]; mp 223° C.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH:27]=O)[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][NH:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][N:32]([CH3:33])[CH3:31])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(C=O)CC3)c2-c2ccccc2)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CC1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarbaldehyde (Examples 14-17 General Procedure, Step A, 0.51 g) in dichloromethane (20 mL) is added sequentially a solution consisting of dimethylamine in tetrahydrofuran (2.0 M, 2 mL) followed by sodium triacetoxyborohydride (0.75 g.) The mixture is agitated overnight at room temperature under a nitrogen atmosphere. The mixture is diluted with dichloromethane (20 mL) and is washed twice with brine solution. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography to afford the synthetic intermediate (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropylmethyl)-dimethyl-amine (0.251 g)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10][CH2:11][CH2:12][CH2:13]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][CH2:11][S:10][CH3:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CSCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CSCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-bromophenol (3.4 g) and 3-methylthio-1-propanol (2.6 g) in tetrahydrofuran (20 mL) were added tributylphosphine (7.5 mL) and 1,1′-(azodicarbonyl)dipiperidine (7.6 g), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (4.6 g, 83%) as a white crystal.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[CH2:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:27]=2)[NH:22][N:21]=1)[CH3:19].[CH:33]1(Br)[CH2:37][CH2:36][CH2:35][CH2:34]1>C(OCC)(=O)C.CN(C=O)C>[CH:33]1([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:24]=3)[C:20]([CH2:18][CH3:19])=[N:21]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reactant: BrC1CCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 337 mg (8.4 mmol) of NaH (60% in mineral oil), 1.7 mL (8.4 mmol) of 15-crown-5 and 42 mL of DMF was added 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. This mixture was stirred at room temperature for 3 hours and then 1.35 mL (12.6 mmol) of cyclopentyl bromide was added and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in 40 mL ethyl acetate, washed with 30 mL of water and 30 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography over SiO2 using a step gradient of 10% ethyl acetate in hexanes until the first compound eluted and then 50% ethyl acetate in hexanes to provide 662 mg (2.4 mmol) of methyl 1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate as a clear oil along with 144 mg (0.53 mmol) methyl 2-(cyclopentyl-3-ethyl)-2H-indazol-6-yl-carboxylate as a yellow oil. 1H-NMR (CDCl3) δ 8.17 (s, 1H), 7.71 (dd, J1=8.4 Hz, J2=6.7 Hz, 2H), 5.0 (p, J=7.5 Hz, 1H), 3.97 (s, 3H), 3.00 (q, J=7.5 Hz, 2H), 2.16 (m, 4H), 1.92 (m, 2H), 1.74 (m, 2H), 1.39 (t, J=7.6 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[NH:7]1)=[O:5])C.O.[OH-].[Li+].O>O1CCCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][CH:6]([C:4]([OH:5])=[O:3])[NH:7]1
Reactant: CCOC(=O)C1CCS(=O)(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCS(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 2-{3-[((S)-3-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (430 mg, approx. 0.96 mmol) in tetrahydrofuran (4 mL) was added lithium hydroxide hydrate (71 mg, 1.7 mmol) followed by water (1 mL). The reaction mixture was stirred at room temperature for 2 h, and then the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The remaining solution was stirred and approximately 25 drops of 1 M hydrochloric acid were added to bring the pH to 4.5. The sample was stirred for 10 min and the aqueous solution was decanted away from the yellow gum. The gum was washed with water (2 mL). The combined aqueous layers were evaporated to dryness, and dried overnight to give 2-{3-[((S)-3-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid as a white residue (200 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[NH:5][CH:6]=1.[Li+].CC([N-]C(C)C)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[NH:5][CH:6]=1.[S:17]([N:5]1[CH:6]=[C:2]([Br:1])[CH:3]=[C:4]1[CH:7]=[O:8])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=Cc1cc(Br)c[nH]1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)cc2C=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 154.4 %

Procedure:
4-Bromopyrrole-2-carboxaldehyde was prepared by the method of Sonnet, P. E., J. Org. Chem. (1971), Vol. 36, p. 1005. A solution of 4-bromopyrrole-2-carboxaldehyde (2.61 g) and tetrahydrofuran (100 mL) was cooled to 0° C. LDA (7.5 mL of a 2 N solution in THF) was added dropwise and the mixture was stirred at 0° C. for 1 hour. Tosyl chloride (2.88 g) was then added. The resulting reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated. The dark colored solid was chromatographed on SiO2 with 4:1 hexane/ethyl acetate to afford N-tosyl-4-bromo-2-pyrrolecarboxaldehyde (3.8 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22]>CC(C)=O>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:23])[CH3:17]
Reactant: CN(C)CCCN
Reactant: COC(=O)/C=C\C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NCCCN(C)C)C(=O)O
Temperature: 25 °C

Procedure:
286 g (2.0 mols+10% excess) of maleic acid-monomethyl ester are placed into a glass flask fitted with a blade stirrer, thermometer, reflux condenser and dropping funnel, and, with ice-water cooling, 400 ml of triethylamine are added dropwise at 6°-11° C. internal temperature within 1 hour and 35 minutes. The cooling is subsequently removed, 204 g (2.0 mols) of 3-dimethylaminopropylamine are quickly added, and the mixture is reacted for 10 minutes at 87°-90° C. and is then cooled to room temperature; the crystalline crude product is mixed with 1 liter of acetone, the suspension is filtered, and the filter residue is washed with acetone. The yield after drying at 80° C. in vacuo is 296 g (63.7% of theory) of a crystalline aspartic acid derivative, which melts at 171°-172° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH:23]([C:26]1[C:30]([C:31]([O:33]CC)=[O:32])=[CH:29][NH:28][N:27]=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:23]([C:26]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]([CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)[N:27]=1)([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1c[nH]nc1C(C)C
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C(=O)O)c(C(C)C)n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
A mixture of 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyloxazole (7.13 g), ethyl 3-isopropyl-1H-pyrazol-4-carboxylate (6.17 g), potassium carbonate (4.72 g) and N,N-dimethylformamide (70 ml) was stirred at 80° C. overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (4.83 g) and ethanol (150 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the mixture, then the mixture was acidified with dilute hydrochloric acid. The crystals obtained were collected by filtration to yield 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylic acid (11.39 g, yield: 78%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 194–195° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Br)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cc(Cl)cc(Br)c1F
Yield: 102.3 %

Procedure:
To a solution of 3-bromo-5-chloro-2-fluoroaniline (SM-5, step 3, 0.52 g, 2.3 mmol) in pyridine (2.5 mL) cooled in an ice water bath was added propane-1-sulfonyl chloride (0.3 mL, 2.8 mmol). After 4 hours the solution was concentrated and partitioned between EtOAc (75 mL) and aqueous 0.1 M HCl solution (30 mL). The layers were separated and the organic phase was then washed with brine, dried (Na2SO4) and concentrated to give 778 mg of N-(3-bromo-5-chloro-2-fluorophenyl)propane-1-sulfonamide as a yellow solid which was carried forward without further purification: LCMS (m/z) not observed, tR=0.95 minute.