Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=O.[C:12]([O:21]CC)(=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH2:18]([O:17][C:15]([C:14](=[CH:10][C:6]1[S:5][CH:9]=[CH:8][CH:7]=1)[CH2:13][C:12]([OH:21])=[O:20])=[O:16])[CH3:19]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccs1)CC(=O)O
Yield: 49 %

Procedure:
Sodium ethylate (41.4 g, 0.61 mol) was added under vigorous stirring to a solution of thiophene-2-carbaldehyde (57 g, 0.51 mol) and diethyl succinate (176 g, 1.01 mol) in ethanol (1 L). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 300 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give 60 g (0.25 mol, 49%) of 3-(ethoxycarbonyl)-4-thien-2-ylbut-3-enoic acid as a light-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:31](O)[CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OCCOCCOCCO
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCCOCCOCCO)cc4CCC3C2C2CCCC2)cc1Cl
Yield: 47 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and triethylene glycol according to Method E (yellow solid, 125 mg, 0.226 mmol, 47% yield). ES-HRMS m/z calc. for C30H34ClN3NaO5 (M+Na) 574.2085, found 574.2047.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:25]([CH2:24][CH2:23][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:43]
Reactant: c1ccc(CNCCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCCN(CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)Cc1ccccc1

Procedure:
A suspension of 3,4-bis(phenylmethoxy)-N-phenylmethyl benzeneethanamine (10 g), ethyl 6-bromohexanoate (10.5 g), potassium carbonate (6.34 g) and potassium iodide (1 g) in acetonitrile (250 ml) was heated under reflux for 24 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13](/[CH:18]=[CH:19]/[C:20]([N:22]2[C@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][O:24][C:23]2=[O:33])=[O:21])[CH:14]=[C:15]([F:17])[CH:16]=1>C1COCC1>[F:10][C:11]1[CH:12]=[C:13]([C@H:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][C:20]([N:22]2[C@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][O:24][C:23]2=[O:33])=[O:21])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: O=C(/C=C/c1cc(F)cc(F)c1)N1C(=O)OC[C@H]1c1ccccc1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: O=C(C[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-fluorophenylmagnesium bromide (29 mL of a 2.0 M solution in THF, 58 mmol) and copper(I) bromide-dimethylsulfide complex (12 g, 59 mmol) in THF (100 mL) under an atmosphere of nitrogen was cooled to −40° C. in a dry ice-acetonitrile bath. To the stirred solution was added a solution of (4R)-3-[(2E)-3-(3,5-difluorophenyl)prop-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (7.7 g, 23 mmol) in 100 mL of THF dropwise over 15 min. The resulting mixture was stirred at −40° C. for 1.5 h, then the cooling bath was removed and the stirred mixture was allowed to warm to ambient temperature. The reaction was quenched by the addition of aqueous NH4Cl solution. The resulting mixture was stirred for 15 min then extracted with two portions of EtOAc. The combined organic phases were washed with water and brine, then dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 330 g SiO2 column using a gradient elution of 0-50% EtOAc:A, where A=1:1 hexanes:CHCl3. Fractions containing product were combined and the solvents were removed in vacuo to give a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c3ccccc3c3ccccc3c2c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc2c3ccccc3c3ccccc3c2c1
Reaction time: 2 h
Yield: 100 %

Procedure:
3.1 g (11.3 mmol) of a mixture of 1 and 2-nitrotriphenylene (synthesized according to J. Chem. Soc., 1955, 4482) in about 100 mL of ethanol, 600 mg (0.57 mmol) of Pd/C (10% on activated carbon), and 2.3 g (45.2 mmol) of hydrazine monhydride were charged in a 250 mL round bottle flask. The reaction mixture was heated up to reflex under nitrogen for 2 hours. The reaction mixture was then filtered and the filtrate was concentrated and passed through a silica gel column using 25% ethyl acetate in hexanes as elute. 1 and 2 aminotriphenyl were separated and confirmed by MS and NMR. This reaction yield was 100%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24].N>O1CCCC1.CO>[NH2:25][C:23]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: Cc1c(-c2ccc3c(c2)OCCO3)sc(N)c1C(N)=O
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(-c2ccc3c(c2)OCCO3)sc(NC(N)=O)c1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Amino-4-methyl-5-(1,4-benzodioxan-6-yl)-3-thiophencarboxamide (0.44 g) was dissolved in tetrahydrofuran (10 ml), cooled to 0° C. and trichloroacetylisocyanate (0.11 ml) added dropwise with stirring. Stirring was continued for a further 30 minutes at room temperature and then a solution of ammonia in methanol (8 ml of a 10% solution) was added and stirring was continued for a further 3 h. The solvent was evaporated and the residue treated with ethyl acetate and the product filtered off.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COCc3ccc4ccccc4c3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxymethyl-phenyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(naphthalen-2-ylmethoxymethyl)-phenyl]-piperidine-1-carboxylate as a colourless oil, Rf : 0.31 (SiO2, hexane:ethyl acetate=2:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(O)C(F)(F)F)cc2n1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)C(F)(F)F)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-6-(2,2,2-trifluoro-1-hydroxyethyl)-benzoimidazole-1-carboxylic acid tert-butyl ester (475 mg) in methylene chloride (15 mL) was added Dess-Martin reagent (527 mg) and the mixture was stirred at ambient temperature for 18 h. The mixture was washed with water and sodium bicarbonate solution then was dried over sodium sulfate. The solvent was removed under reduced pressure to give 2-(2,6-dimethylphenyl)-6-(2,2,2-trifluoroacetyl)-benzoimidazole-1-carboxylic acid tert-butyl ester as a gummy solid. The material was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1([O:15][CH2:16][CH2:17][CH:18]=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:27][C:28](=[O:30])[CH3:29])C=CC=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1([O:15][CH2:16][CH2:17]/[CH:18]=[CH:27]/[C:28](=[O:30])[CH3:29])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(OCCC=O)CC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)/C=C/CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of tert-butyl 4-methyl-4-(3-oxopropoxy)piperidine-1-carboxylate (5.7 g, 21.01 mmol) in CH2Cl2 (150 mL) was added 1-(triphenylphosphoranylidene)propan-2-one (8.69 g, 27.3 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-40% EtOAc/hexane) to afford (E)-tert-butyl 4-methyl-4-((5-oxohex-3-en-1-yl)oxy)piperidine-1-carboxylate (5.25 g, 16.86 mmol, 80% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.85 (dt, J=16.1, 6.9 Hz, 1H), 6.15 (dt, J=16.0, 1.4 Hz, 1H), 3.79-3.66 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.12 (t, J=11.6 Hz, 2H), 2.49 (qd, J=6.5, 1.5 Hz, 2H), 2.29-2.26 (m, 3H), 1.73 (d, J=13.2 Hz, 2H), 1.47 (s, 9H), 1.46-1.39 (m, 2H), 1.18 (s, 3H). LCMS (M+Na)=334.3.
Reaction SMILES: [C:1]1([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1.[H-].[Na+]>CN(C)C=O>[C:2]1([C:7]2[N:11]([CH2:12][CH2:10][CH2:9][CH2:15][CH3:14])[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:16]1[N:17]([CH2:3][CH2:2][CH2:1][CH2:6][CH3:5])[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)c(-c2nc3ccccc3[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1c(-c2ccccc2-c2nc3ccccc3n2CCCCC)nc2ccccc21
Reaction time: 0.5 h

Procedure:
To a flask were added 1.5 g of 2,2′-(1,2-phenylene)bis(1H-benzimidazole) and 30 ml of N,N-dimethylformamide, and the mixture was cooled to 5 C. To this mixture was added 0.48 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 5-10 C for 30 minutes, 2.4 g of 1-1-iodopentane were added. The reaction mixture was warmed to 22 C for and stirred for 16 hours, then quenched with 50 ml water. The product was extracted with 40 ml ethyl acetate and following removal of the solvent, the product was purified by silica gel chromatography using 25% ethyl acetate, 75% hexane and 0.1% triethylamine resulting in 2.1 g of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[CH3:11]C(C)([O-])C.[K+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:11])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Br)cc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-bromo-2-fluoro-benzaldehyde (Aldrich, 2.30 g, 11.3 mmol) and methyltriphenylphosphonium bromide(Aldrich, 4.93 g, 13.6 mmol) in ether (50 mL), potassium tert-butoxide(1.52 g, 13.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solid was filtered off and the filtrate was concentrated. The residue was treated with 30% ethyl acetate/hexanes (3 mL) and the solid was removed by filtration. The filtrate was filtered through a silica gel pad eluting with 30% ethyl acetate/hexanes to give a yellow oil. 1.54 g, 68%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22](Cl)=[O:23])[CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[CH3:12][C:11]([C:7]1[CH:8]=[C:9]([C:22]([C:19]2[CH:18]=[C:17]([CH3:16])[O:21][N:20]=2)=[O:23])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 20.6 g (0.1 mole) of 2,6-di-tert-butylphenol and 15.6 g (0.107 mole) of 5-methylisoxazole-3-carboxylic acid chloride in 100 mL of CS2 is added 14.3 g (0.107 mole) of AlCl3 at +5° C. Vigorous stirring is maintained at that temperature for 1 hour and then at room temperature for 1 hour. The CS2 is decanted off and the residue treated with 350 mL of ice cold IN HCl and extracted with Et2O. The extracts are washed with saturated NaHCO3 solution and brine, dried with Na2SO4 and evaporated to give a mixture of products. The desired product is separated by flash chromatography (0% to 50% CH2Cl2 /n hexane) on silica gel to give 4.4 g of the crude ketone which is recrystallized from n-pentane to give 2.3 g (14%) of pale yellow crystals, [3,5-bis(1,1 dimethylethyl)-4 -hydroxyphenyl(5-methyl-3-isoxazolyl)methanone, mp 120° C.; 1H NMR (CDCl3)δ1.48 (s, 18H, tert-butyl), 2.52 (s, 3H, CH3), 5.85 (s, 1H, OH), 6.48 (s, 1H, isoxazole aromatic), 8.23 (s, 2H, phenyl aromatics); IR (KBr) 1590, 1600, 1650, 3600 cm-1 ; MS (DEI) m/e 315 (M+), 300 (M-CH3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:8])[CH3:7].[CH:9]([C:12]1[N:16]=[C:15]([C:17](OCC)=[O:18])[S:14][N:13]=1)([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:8][C:17]([C:15]1[S:14][N:13]=[C:12]([CH:9]([CH3:11])[CH3:10])[N:16]=1)=[O:18])[CH3:7]
Reactant: CCOC(=O)c1nc(C(C)C)ns1
Reactant: CC(N)c1cccs1
Solvent: Cc1ccccc1
Product: CC(C)c1nsc(C(=O)NC(C)c2cccs2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
(R/S)-1-Thiophen-2-yl-ethylamine (19.05 g, 0.150 mol) is added to a stirred solution of ethyl 3-isopropyl-[1,2,4]thiadiazole-5-carboxylate (25.0 g, 0.125 mol) in toluene (50 ml) and the mixture is heated to 80° C. for 2 hours. A further portion of (R/S)-1-[(2-thienyl)ethyl]amine (10.0 g, 0.08 mol) is added to the mixture, which is heated at 80° C. for a further 2 hours. Then a further portion of (R/S)-1-[(2-thienyl)ethyl]amine (10.0 g, 0.08 mol) is added to the mixture, and stirring is continued for a further 3 hours at 80° C. The solvent is evaporated in vacuo, and the residue is dissolved in methyl tert-butyl ether. The resulting solution is washed two times with 1N hydrochloric acid, dried with magnesium sulphate and the solvent is evaporated in vacuo. The oily residue is dissolved in petroleum ether (50 ml) and, upon agitation, the product crystallises out of the solution. The crystalline product is filtered off, washed with a small amount of petroleum ether and dried, to give (R/S)-3-isopropyl-[1,2,4]thiadiazole-5-carboxylic acid, [1-(2-thienyl)ethyl]amide (22.3 g, 63%) as beige crystals, m.p. 61°-63° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][O:25][CH:26]1[CH2:29][NH:28][CH2:27]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:29][CH:26]([O:25][CH2:24][C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1csc(COC2CNC2)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-(2-thienylmethoxy)azetidine hydrochloride (29 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a brown solid. This solid was triturated in acetone and diethyl ether, filtered, washed with diethyl ether then dried to give the title compound (8 mg, 18%) as a pale brown solid.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([S:13][C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].O>Cl.C1COCC1>[CH:3]([C:4]1[CH:5]=[C:6]([S:13][C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:2]
Reactant: COC(OC)c1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(3-dimethoxymethyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.027 mol) in 12N HCl (25 mL), THF (75 mL), and water (50 mL) was stirred overnight at room temperature, and then the mixture was extracted with EtOAc. The extract was washed with H2O and then with a saturated Na2CO3 solution. The solvent was evaporated, and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[Br:20]Br>C(Cl)Cl>[Br:20][C:11]1[CH:12]=[CH:13][C:5]([O:4][CH2:3][C:2]([F:14])([F:15])[F:1])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccccc1OCC(F)(F)F
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1cc(Br)ccc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)benzoic acid (22 g) in methylene chloride (100 ml), was added AlCl3 (13.3 g) at 0° C.followed by bromine (16.0 g, 0.1 mol). The reaction mixture was stirred at 0° C. for 1 hour and then at reflux for 2 hours. The solids were filtered and water (50 ml) and ethyl acetate (50 ml) were added to the filtrate. The aqueous layer was separated and extracted with ethyl acetate (2×60 ml) and the combined organic layers were washed with water (2×60 ml). The organic layer was concentrated under vacuum to dryness and hexane (100 ml) was added and the resulting suspension was stirred at 20 to 25° C. for 1 hour. The mixture was filtered and the cake was rinsed with heptanes (2×20 ml). The damp solids were dried in vacuum at 45° C. for 5–6 hours to give a white solid (28.3 g, yield 94.6%), m.p. 126–128° C.
Reaction SMILES: [ClH:1].Br[C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[S:5][C:4]=1[NH2:12]>CO.[Pd]>[ClH:1].[S:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[C:4]1[NH2:12]
Reactant: Nc1sc2cccnc2c1Br
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cc2ncccc2s1
Reaction time: 3 h
Yield: 56.5 %

Procedure:
A mixture of compound 145-H, (1.86 g, 6.16 mmol) and 10% Pd/C (0.49 g, 26.3% w/w) in methanol (75 mL) was catalytically hydrogenated on a Parr shaker at 25 psi. After 3 h, the catalyst was filtered, the reaction mixture recharged with 10% Pd/C (0.49 g, 26.3% w/w) and shaken an additional 16 h at 22 psi H2. The reaction was filtered, recharged with 10% Pd/C (0.20 g, 10.8% w/w), and shaken at 20 psi H2 for an additional 24 h. The reaction mixture was filtered, evaporated, and the free base isolated by washing with aqueous sodium bicarbonate. The resultant residue was purified by flash column chromatography (SiO2), eluting with 3% MeOH/CH2Cl2 to afford compound 146-A as a yellow solid (0.65 g, 57%). 1H-NMR (DMSO-d6): δ 6.4 (s, 1H), 7.1 (dd, 1H), 8.3 (2, 1H), 8.4 (s, 2H), 8.5 (d, 1H), 15.2 (br s, 1H); MS: m/z 151.1 (MH+).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)=[CH:9]2)(=O)[CH2:2][CH2:3][CH3:4].[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][N:33]=[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)=[CH:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCCC(=O)c1ccc2c(c1)cc(C1CCN(C(=O)OC(C)(C)C)C1)n2C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc(C1CCN(C(=O)OC(C)(C)C)C1)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of tert-butyl 3-(5-butyryl-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (0.823 g, 2.22 mmol) in DCM (5 mL) was added 2,4-dimethoxybenzylamine (0.38 mL, 2.53 mmol) and NEt3 (0.90 mL, 6.45 mmol). Mixture was cooled to 0° C. before TiCl4 solution (1M DCM, 1.45 mL, 1.45 mmol) was added dropwise via syringe pump over 30 min. Reaction was allowed to warm to room temperature and stirred overnight. Mixture was diluted with DCM (10 mL) and then quenched with NaHCO3 (aqueous saturated, 10 mL). Upon vigorous shaking organic phase was separated using a PTFE phase separator, dried over Na2SO4. Removal of the solvent afforded product (1.15 g, quant) as yellow oil, which was taken directly into next steps without purification.