Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:23][N:9]1[C:8](=[O:18])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[C:13]=2[S:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=2
Reactant: CI
Reactant: O=C1Nc2ccccc2Sc2c1cccc2C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cccc(C(F)(F)F)c2Sc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 4-trifluoromethyl-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.295 g, 1 mmol) in DMF (20 ml) was added sodium hydride (0.1 g of 60% dispersion in oil) and the resulting mixture stirred for 30 minutes, before methyl iodide (1 equivalent) was added. After stirring for 1 hour the mixture was evaporated and the residue separated between ethyl acetate and aqueous sodium bicarbonate. The organic fractions were dried (magnesium sulphate) and evaporated. Purification of the residue by chromatography on silica, eluting with ethyl acetate/petrol (1:1, v/v), followed by recrystallisation from cyclohexane gave the title compound as colourless needles (0.121 g, m.p. 139°-141°, Rf 0.41 [silica, ethyl acetate/petrol, 1:2, v/v]).
Reaction SMILES: [CH2:1]([S:3]([C@@H:6]1[N:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[C@H:7]1[CH2:14][CH2:15][CH2:16][N:17](C(OCC1C=CC=CC=1)=O)[C:18]([NH:20]C(OCC1C=CC=CC=1)=O)=[NH:19])(=[O:5])=[O:4])[CH3:2].[ClH:41]>[Pd].CO.C(OCC)(=O)C>[ClH:41].[CH2:1]([S:3]([C@@H:6]1[N:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[C@H:7]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)[C@H]1[C@H](CCCN(C(=N)NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS(=O)(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 62 %

Procedure:
A methanol/ethyl acetate (2.5 mL/2.5 mL) solution of compound 22 (380 mg, 0.66 mmol) and lN HCl (0.66 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material. The suspension was filtered through a pad of Celite, and the solution was concentrated to afford 140 mg (62%) of the product as a yellow foam.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Si:14]([O:9][C@@H:3]([CH2:2][Cl:1])[CH2:4][C:5]([O:7][CH3:8])=[O:6])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C[C@@H](O)CCl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@H](CCl)O[Si](C)(C)C(C)(C)C
Yield: 113.9 %

Procedure:
A solution of (R)-methyl 4-chloro-3-hydroxybutanoate (15 g, 98.7 mmol) in CH2Cl2 (240 mL) was stirred overnight with tert-butyl-chloro-dimethyl-silane (17.82 g, 118.2 mmol), imidazole (33.6 g, 493.5 mmol) and a catalytic amount of DMAP (0.6 g, 4.92 mmol) at room temperature under N2. The reaction mixture was poured into water (150 mL) and acidified to pH 6-7 by dropwise addition of cold aqueous HCl (0.5 M). The aqueous phase was extracted with CH2Cl2 (3×60 mL). The combined organic phases were washed with sat. Na2CO3 solution, brine, dried over anhydrous Na2SO4 and concentrated to give (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (30 g, crude).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=O>O1CCCC1>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=CCCCCCCCCCBr
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C\CCCCCCCCCBr
Yield: 64.6 %

Procedure:
60 g (0.13 mol) of (5-carboxypentyl)triphenylphosphonium bromide were suspended in 250 ml of tetrahydrofuran. 30 g (0.26 mol) of potassium t-butylate in 20 ml of tetrahydrofuran were then added. Subsequently, 26 g (0/11 mol) of 10-bromodecanal were added. After usual work up 28 g (65%) of crude 6Z-16-bromohexadec-6-enoic acid were obtained having the following characteristics: Z/E=93/7;
Reaction SMILES: [OH:1][CH:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:12].[H][H]>CO.[Pd]>[ClH:12].[OH:1][CH:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: CS(=O)(=O)OCC(O)CC#N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)OCC(O)CCN

Procedure:
To a solution of (RS)-3-hydroxy-4-(methanesulfonyloxy)butyronitrile (14.6 g) in methanol (60 ml), 10 wt. % Pd on carbon (2.5 g) and conc. hydrochloric acid (15 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4.0 kg/cm2 at room temperature for 8 hours. After filtering off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 1/9) to obtain pure (RS)-3-hydroxy-4-(methanesulfonyloxy)butylamine hydrochloride (15.4 g). Yield, 85 %.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[C:39](N1C=CN=C1)([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)=[O:40].P([O-])([O-])([O-])=O>ClCCl.[H-].[Na+]>[N:41]1([C:39]([O:38][C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@H:10]([S:12][C@@H:13]2[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=3[F:31])[O:15][CH2:14]2)[CH3:11])=[O:40])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)n1ccnc1)c1ccc(F)cc1F
Yield: 69.6 %

Procedure:
4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (4.90 g, 9.03 mmol) described in Reference example 1 and 1,1′-carbonyldiimidazole (1.53 g, 9.44 mmol) were dissolved in dichloromethane (20 ml). To the mixture was added sodium hydride (55% dispersion in mineral oil; 10 mg, 2.3×10−4 mol), and the reaction mixture was heated under reflux for 3 hours with stirring. After cooling, a phosphate buffer solution (pH 7.4) was added thereto, and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (120 g) column (eluent; ethyl acetate:hexane=1:1˜1:0) to afford the title compound (4.00 g, 70% yield) as a colorless amorphous solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)CCCO1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylpiperazine (2.0 g, 1.9 mL, 12.3 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.53 g, 12.9 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound K, 3.04 g (87%).
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:12]3[C:8]([CH2:9][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([OH:21])C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[C:2]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])[CH3:1]
Reactant: CCO
Reactant: Cc1c(-c2ccccc2)c2cccc3c2n1CC3
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(c1ccccc1)c1cccc2c1NCC2

Procedure:
A mixture of 6.0 g. (0.0258 mole) of 1,2-dihydro-4-methyl-5-phenylpyrrolo[3,2,1-hi]indole in 60 ml. of ethanol, 30 ml. of water and 30 ml. of conc. sulfuric acid was refluxed for one hour. The hot solution was poured into a cold concentrated sodium hydroxide solution and the basic solution was extracted several times with ether. The combined ether extracts were washed with water, dried over sodium sulfate and concentrated at reduced pressure. The residual oil solidified and was recrystallized from petroleum ether to give 7-(α-acetylbenzyl) indoline which melted at 55°-56°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH2:20]Br)[CH:13]=2)[O:9][N:8]=1.[NH3:22]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH2:20][NH2:22])[CH:13]=2)[O:9][N:8]=1
Reactant: N
Reactant: N#Cc1cc(CBr)cc(-c2nc(-c3ccccn3)no2)c1
Solvent: ClCCl
Product: N#Cc1cc(CN)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 50 °C
Yield: 0.8 %

Procedure:
A solution of 3-(2-pyridyl)-5-(3-bromomethyl-5-cyanophenyl)-1,2,4-oxadiazole (0.5 g, 1.91 mmol) in dichloromethane (1.5 mL) was treated with a 0.5M ammonia (1.5 mL, 1.5 mmol, dioxane) and heated at 50° C. for 90 minutes. After this time the reaction mixture was cooled and diluted with dichloromethane. The organic solution was washed with water and brine. Silica gel chromatography of the crude product afforded 3.5 mg (5.5%) of 3-(2-pyridyl)-5-(3-aminomethyl-5-cyanophenyl)-1,2,4-oxadiazole.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:20][CH3:21].[C:22]([Cu])#[N:23].CN(C=O)C>C(OCC)(=O)C>[CH3:21][O:20][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=2)[C:2]=1[C:22]#[N:23]
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3c(C#N)c(OC)ccc3c2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29.7 %

Procedure:
A mixture of 1-bromo-2-methoxy-6-(4-methoxyphenyl)naphthalene (0.76 g, 2.21 g), CuCN (0.24 g, 2.66 mmol) and DMF (10 mL) was stirred at 120° C. for 4 hr. The reaction mixture was cooled to room temperature, slurried with ethyl acetate, filtered through silica, and evaporation of the solvent, and purification by silica column chromatography (20% ethyl acetate-hexanes) yielded 0.19 g (30%) of the title compound as a pale yellow solid: mp 182–185° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.09 (3H, s), 7.03 (2H, d, J=8.73 Hz), 7.29 (1H, d, J=9.12 Hz), 7.63 (2H, d, J=8.73 Hz), 7.88 (1H, dd, J=1.98 Hz, J=8.73 Hz), 7.97 (1H, d, J=1.98 Hz), 8.09 (1H, d, J=9.12 Hz), 8.14 (1H, d, J=8.73 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]>>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:16]2[CH2:15][CH2:14][N:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([O:6][C:5]4[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:12]=3)[CH2:18][CH2:17]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: Clc1ccc(Oc2cccc(N3CCNCC3)n2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(Oc4ccc(Cl)cc4)n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-[6-(4-chloro-phenoxy)-pyridin-2-yl]-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12]([O:14]CC)=[CH2:13])=[C:7]([Cl:17])[N:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12](=[O:14])[CH3:13])=[C:7]([Cl:17])[N:6]=1)=[O:4]
Reactant: C=C(OCC)c1nc(N)c(C(=O)OC)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(Cl)c(C(C)=O)nc1N
Yield: 105.4 %

Procedure:
A solution of 3-amino-6-chloro-5-(1-ethoxy-vinyl)-pyrazine-2-carboxylic acid methyl ester (46 mg, 0.190 mmol) and para-toluenesulfonic acid monohydrate (73.8 mg, 0.388 mmol) in THF (2.85 ml) was stirred at rt for 1 h. Saturated aq. NaHCO3 was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow solid (46 mg). This material was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30]CS([O-])(=O)=O)(=[O:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CS(=O)(=O)Oc1ccccc1CCCS(=O)(=O)[O-]
Product: CCOC(=O)C(Cc1ccc(OCCc2ccccc2OS(C)(=O)=O)cc1)OCC

Procedure:
2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester was alkylated with 2-(2-methanesulfonyloxyphenyl)ethylmethanesulfonate using the same method as in Example 1 (b) to give 2-ethoxy-3-{4-[2-(2-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][C:4]1=[O:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH2:1]([N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[C:6]([N+:15]([O-:17])=[O:16])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)cc(O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21
Temperature: 100 °C

Procedure:
A suspension of 1-ethyl-4-hydroxy carbostyril (1.09 g; 0.00575 mole) in glacial acetic acid (5 ml) was swirled during the rapid addition of concentrated nitric acid (1.25 ml; d 1.42) and the dark liquid heated for 5 minutes at 100° C. The yellow solid which separated on cooling was filtered off and washed well with ethanol m.p. 154°-5° C (decomp). (Found; C, 56.54; H, 4.52; N, 11.56; C11H10N2O4 requires; C, 56.41; H, 4.30, N, 11.96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16]([C:17]#[N:18])[C:9]=23)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:37]I>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:15]([I:37])=[C:16]([C:17]#[N:18])[C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1c(C#N)cn2COCC[Si](C)(C)C
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2c1c(C#N)c(I)n2COCC[Si](C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 248B (0.7 g, 1.76 mmol) in tetrahydrofuran (50 mL) was cooled to −75° C. and treated dropwise with 2N lithium diisopropylamide in tetrahydrofuran (1.7 mL, 3.40 mmol). The mixture was stirred at −75° C. for 30 minutes and iodine (0.85 g, 3.52 mmol) in 2.5 mL tetrahydrofuran was added. The mixture was slowly brought to room temperature and quenched with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (twice). The organic layers were concentrated and purified by column chromatography (Combi Flash Rf) (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 524 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10]2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:13]2[CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10][C:9]2=[N:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[CH:18]([CH3:20])[CH3:19])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: CC(C)c1cc(I)ccc1N=C1NCC2(CCCC2)S1
Product: CC(C)c1cc(I)ccc1N=C1SC2(CCCC2)CN1C1CCCC1

Procedure:
2-Isopropylaniline was converted to 4-iodo-2-isopropylaniline according to Method A5a. The aniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-isopropylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-isopropylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-isopropylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-isopropylphenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH:25]1([NH:28][C:29](=[O:46])[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([C:2]3[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH2:15][N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[O:7])=[CH:4][N:3]=3)[CH:31]=2)=[O:46])[CH2:26][CH2:27]1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.36 min, MH+ 484. NMR: δH [2H6]-DMSO 11.70,(1H, b), 9.23,(1H, s), 8.50,(1H, d), 8.38,(1H, d), 8.33,(1H, d), 7.92,(1H, s), 7.83,(2H, m), 7.43,(1H, d), 7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.77,(2H, s), 2.87,(1H, m), 2.67-2.24,(11H, m), 2.13,(3H, s), 0.70,(2H, m), 0.58,(2H, m).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)[CH3:2].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)[CH:7]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cn(Cc2ccc([N+](=O)[O-])cc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
A mixture of 4-ethyl-1H-imidazole (2.46 g), 4-nitrobenzyl bromide (6.08 g), potassium carbonate (7.08 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 4-ethyl-1-(4-nitrobenzyl)-1H-imidazole (1.95 g) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, v/v). A mixture of 4-ethyl-1-(4-nitrobenzyl)-1H-imidazole (1.95 g), 10% palladium carbon (200 mg) and ethanol (50 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 1-(4-aminobenzyl)-5-methyl-1H-imidazole (1.44 g) as colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cccc([N+](=O)[O-])c5n4)cc3CC[C@@H]12
Yield: 54.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-8-nitro- quinoline (96 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80-100% ethyl acetate/hexanes eluent) to give 90 mg (55%) of the title compound as a solid. mp 199°-200°. FDMS: m/e=433. α[D]589 =+76.80 (c=0.42, chloroform).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10]([CH3:13])(=O)=O)=[C:5]2[C:4](=[O:22])[CH2:3]1.[OH-].[Na+].SC1[S:28][CH:29]=[CH:30][N:31]=1>CCO>[CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10][C:13]3[S:28][CH:29]=[CH:30][N:31]=3)=[C:5]2[C:4](=[O:22])[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C(=O)N3CCCC3)c2C1
Reactant: Sc1nccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)c2c(Sc3nccs3)sc(C(=O)N3CCCC3)c2C1
Temperature: 70 °C
Yield: 27.8 %

Procedure:
To a suspension of 6,6-dimethyl-3-methanesulphonyl-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (400 mg, 1.1 mmol) in EtOH (10 mL) was added NaOH (1.1 mL of a 3 M solution, 3.3 mmol) followed by 2-mercaptothiazole (0.39 g, 3.3 mmol). The mixture was heated at 70° C. for 5 h then the solution was evaporated. The residue was partitioned between EtOAc (20 mL) and NaOH (1 M; 30 mL). The organic phase was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with EtOAc:hexane (2:1), to afford the title compound (120 mg. 28%) as a colourless solid. 1H NMR (250 MHz, CDCl3) δ 1.07 (6H, s), 1.90-1.95 (4H, m), 2.45 (2H, s), 2.83 (2H, s), 3.40-3.62 (4H, m), 7.55 (1H, d, J=3.4 Hz), 7.97 (1H, d, J=3.4 Hz). MS (ES+) 393 (M+1).