Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:7]=1)=[O:5])C.[OH-].[K+].Cl>CO>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]=2[CH3:11])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 94.5 %

Procedure:
To a solution of the ester 3a (1.0 g, 2.44 mmol) in methanol (25 mL) was added potassium hydroxide (1.0 g, 17.86 mmol) in one portion. The resulting mixture was heated at 60° C. for 4 h. The reaction mixture was then poured into ice water, and the pH of the mixture was adjusted to acidic with addition of 10% hydrochloric acid. The precipitate formed was collected by filtration, washed with water, and dried under vacuum to give carboxylic acid 4a (0.88 g, 94%) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:22][C:23]3[C:24]([CH3:34])=[N:25][C:26]([NH:29][CH2:30][CH2:31][O:32]C)=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].I[Si](C)(C)C>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:22][C:23]3[C:24]([CH3:34])=[N:25][C:26]([NH:29][CH2:30][CH2:31][OH:32])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: COCCNc1ccc(Nc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2OC)c(C)n1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: COc1c(Nc2ccc(NCCO)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To a solution of 4-{5-methoxy-6-[6-(2-methoxy-ethylamino)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester (HCl salt, 101 mg, 0.2 mmol) in 10 mL of CH2Cl2, iodotrimethylsilane (142 μl, 1 mmol) was added at room temperature. The mixture was stirred at the same temperature. After 2 hr, the mixture was purified by HPLC and converted to HCl salt by adding 2 mL of 4M HCl in dioxane solution and concentrated to give 4-{6-[6-(2-hydroxy-ethylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester (Compound 78) (HCl salt, 37 mg, 37%). 1HNMR (CD3CN-d3, 400 MHz) δ 1.12-1.14 (d, 6H), 1.66-1.68 (m, 2H), 1.84-1.89 (m, 2H), 2.35 (s, 3H), 3.27-3.32 (m, 2H), 3.41 (s, 2H), 3.61 (s, 4H), 3.82 (s, 3H), 4.72-4.78 (m, 1H), 5.28 (m, 1H), 6.88-6.90 (m, 1H), 6.69-7.71 (m, 1H), 7.99 (s, 1H) 8.18 (s br, 1H), 8.42 (s br, 1H). Exact mass calculated for C22H32N6O5 460.24. found 461.5 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:37])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[CH2:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:53][CH:54]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
A solution of triphenylphosphine (212 mg, 0.81 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (144 mg, 0.81 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (250 mg, 0.73 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (279 mg, 1.61 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography, (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate), to afford N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (121 mg, 33%) as a white foam: mp 80-83° C. (foam to gel); FAB-HRMS m/e calcd for C20H22BrN3O5S (M+H)+496.0542, found 496.0543.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH:4]=1.Cl.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][O:9][C:5]2[CH:4]=[C:3]([NH:2][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:8]=[CH:7][CH:6]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(CCOc2cccc(N)c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(CCOc2cccc(NS(=O)(=O)c3ccccc3)c2)cc1
Reaction time: 72 h
Yield: 87 %

Procedure:
To a cold (ice:water temperature) solution of amino-3-[2-(4-cyanophenyl)ethoxy]benzene×HCl (231 mg; 0.84 mmol; from step (iii) above) in pyridine (2 mL) was added benzenesulfonyl chloride (119 μL; 0.93 mmol) and the mixture was allowed to reach room temperature and stirred for three days. The pyridine was removed by evaporation and the residue was partitioned between water and EtOAc. The phases was separated and the water phase was extracted twice with EtOAc and the combined organic phase was washed once with 1M KHSO4, brine and dried (Na2SO4). The solvent was evaporated and the residue was subjected to purification by flash chromatography using a stepwise gradient of toluene:EtOAc (100:0, 90:10, 80:20, 60:40 and 40:60) as eluent to give 277 mg (87%) of the sub-title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Cl>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: ClCc1cccc(Cl)c1
Product: O=C1CCN(Cc2cccc(Cl)c2)CC1

Procedure:
1-(3-Chlorobenzyl)-4-piperidone is prepared from 4-piperidone and 3-chlorobenzyl chloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Br[CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[N-:19]=[N+:20]=[N-:21].[Na+].CN(C)C=O>C(Cl)(Cl)Cl>[N:19]([CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CN=[N+]=[N-])O3
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To 2-Bromomethyl-5,8-dimethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (3.36 g, 10.9 mmol) and sodium azide (5.1 g, 78.5 mmol), dimethylformamide (73.2 ml) were added, and stirred for 1 hour in a bath at 100° C. After cooling, the mixture was condensed, and the resultant residue was dissolved in chloroform, which was washed with water and dried. After condensation, the precipitated crystals were subjected to recrystallization (chloroform-ether) to obtain 2.76 g of the title compound as colorless crystals (93.8%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[O:23])[CH2:13][CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>ClCCl>[CH3:15][CH:14]([CH3:16])[CH2:13][C:12]([C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[O:23])=[O:11]
Reactant: CC(C)CC(O)c1occc1C(=O)OC[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)c1occc1C(=O)OC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
Dimethylsulfoxide (125 μl) was dissolved in dichloromethane (10 ml) and cooled to −78° C. Oxalyl chloride (80 μl) was added dropwise and the mixture was stirred for 15 minutes. Trimethylsilylmethyl 2-(1-hydroxy-3-methylbutyl)furan-3-carboxylate (200 mg) in dichloromethane (10 ml) was added and the mixture was stirred for 20 minutes. Triethylamine (0.49 ml) was added. The mixture was stirred for 20 minutes, and then allowed to warm to ambient temperature. The mixture was poured onto water and then extracted thrice with ethyl acetate. The organic phases were combined, washed with brine, dried, filtered and evaporated to give the sub-title compound (170 mg).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1)#[CH:2].[OH:20][N:21]=[C:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC>C1COCC1>[C:23]1([C:22]2[C:1]([C:3]3[C:8](=[O:9])[CH:7]=[CH:6][N:5]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=4)[N:4]=3)=[CH:2][O:20][N:21]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: ON=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1conc1-c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
To a solution of 3-ethynyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (104 mg, 0.391 mmol) and N-hydroxybenzenecarboximidoyl chloride (122 mg, 0.782 mmol) in THF (5 mL) was added Et3N (0.108 mL, 0.782 mmol) at 0° C. The suspension was stirred at room temperature for 14 h. The reaction was quenched with water. The mixture was extracted with AcOEt, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=50/50 to 0/100) and on basic silica gel (hexane/AcOEt=50/50 to 43/57) and crystallized with AcOEt/heptane to yield the title compound (82.4 mg, 55% yield) as a white solid: mp 217-219° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.87 (1H, d, J=8.0 Hz), 7.50-7.59 (3H, m), 7.86-7.92 (2H, m), 7.94-8.02 (3H, m), 8.15-8.26 (2H, m), 9.09 (1H, d, J=8.2 Hz). Anal. Calcd for C20H12F3N3O2: C, 62.67; H, 3.16; N, 10.96. Found: C, 62.60; H, 3.19; N, 10.95.
Reaction SMILES: C(C(C(OCC)=O)C(OCC)=O)C1C=CC=CC=1.[CH2:19]([C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])([CH2:32][C:33]#[CH:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1C=CC=[CH:22][CH:21]=1.BrCC#CC.C(C(C(OCC)=O)(CC#CC)C(OCC)=O)C1C=CC=CC=1>>[C:35]([C:26]([CH2:32][C:33]#[CH:34])([CH2:19][CH2:20][CH2:21][CH3:22])[C:27]([O:29][CH2:30][CH3:31])=[O:28])([O:37][CH2:38][CH3:39])=[O:36]
Reactant: C#CCC(Cc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: CC#CCBr
Agent: CC#CCC(Cc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Product: C#CCC(CCCC)(C(=O)OCC)C(=O)OCC

Procedure:
Proceeding similarly, but replacing diethyl n-butylmalonate with diethyl benzylmalonate, ethyl 2-benzyl-2-carboethoxypent-4-ynoate was prepared. Also by replacing diethyl n-butylmalonate with diethyl benzylmalonate, replacing propargyl bromide with 1-bromo-2-butyne, ethyl 2-benzyl-2-carboethoxyhex-4-ynoate was prepared.
Reaction SMILES: O=S(Cl)Cl.Br.[NH2:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8]([OH:10])=[O:9].[CH3:14]O>>[BrH:13].[CH3:14][O:9][C:8](=[O:10])[C@@H:7]([NH2:6])[CH2:11][CH2:12][Br:13]
Reactant: CO
Reactant: NC(CCBr)C(=O)O
Agent: Br
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCBr
Reaction time: 0.5 h

Procedure:
SOCl2 (7.0 mL) was added slowly to MeOH (100 mL) at −20° C. (bath temp), and stirred for 30 min. 2-Amino-4-bromo-butyric acid hydrobromide (5.0 g, 19 mmol) was then added and the reaction mixture was stirred O/N at rt. Concentration in vacuo gave the title compound as a viscous liquid which become solid on standing: yield 5.2 g (99%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:29][N:31]=2)[CH2:36][CH2:35]1
Reactant: NC(=NO)C1CC1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 26.9 mg (0.269 mmol) of N′-hydroxycyclopropanecarboximidamide (Example 78A) were reacted according to the General Method 1. Yield: 78.3 mg (66% of theory).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([F:20])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:14]1[CH:13]=[CH:12][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:15]=1[N+:17]([O-:19])=[O:18]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1F
Yield: 96.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.8 g) was added to a mixture of benzeneboronic acid (3.1 g), 5-bromo-2-fluoronitrobenzene (5 g) and 22 mL of 2M sodium carbonate solution in toluene (50 mL) and ethanol (50 mL). The mixture was heated to reflux for 2 hours, concentrated, and the residue was extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried, and concentrated to give a yellow oil. The oil was purified by column chromatography on silica gel in 5% ethyl acetate in hexane to give 4.75 g (96% yield) of 4-fluoro-3-nitrobiphenyl as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][C@H:4]([CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:3]([OH:27])=[O:2])(=[O:17])=[O:18])=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To 1.3 mmol of 2(R)-[(4-methoxybenzenesulfonyl)amino]-3-(3-indolyl)-propanoic acid methyl ester suspended in 15 mL of ethanol is added 5 mL of aqueous 2.5M sodium hydroxide. The solid suspension dissolved, and is allowed to stir at ambient temperature overnight. The mixture is acidified with aqueous 10% HCl and extracted with ethyl acetate. The organic phase is washed with brine and dried over sodium sulfate. It is concentrated to afford 0.45 g (93%) of a white solid,
Reaction SMILES: C(O[CH:5]1[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][O:6]1)(=O)C.[CH2:18]([Si](C)(C)C)[CH:19]=[CH2:20].[Sn](Br)(Br)(Br)Br>C(Cl)Cl>[CH2:20]([CH:5]1[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][O:6]1)[CH:19]=[CH2:18]
Reactant: CC(=O)OC1CC(OCc2ccccc2)CO1
Reactant: C=CC[Si](C)(C)C
Agent: Br[Sn](Br)(Br)Br
Solvent: ClCCl
Product: C=CCC1CC(OCc2ccccc2)CO1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a stirred solution of 4-(benzyloxy)tetrahydrofuran-2-yl acetate (3.57 g, 15.11 mmol) and allyltrimethylsilane (9.65 mL, 60.4 mmol) in CH2Cl2 (200 mL) at −78° C. was added a solution of tin(IV) bromide (7.95 g, 18.13 mmol) in CH2Cl2 (20 mL) over 15 min. After 1 h, the ice bath was removed and stirring continued at room temperature for 3 h. The CH2Cl2 was removed using a rotoevaporator and the residue taken up in 1:1 Et2O/hexane (200 mL), washed with sat. Na2CO3 (2×50 mL), water (2×50 mL) followed by brine (50 ml), then dried (Na2SO4), filtered and concentrated to give 2-allyl-4-(benzyloxy)tetrahydrofuran (3.15 g, 14.43 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ: 7.27-7.39 (5 H, m), 5.76-5.90 (1 H, m), 5.03-5.15 (2 H, m), 4.49 (1.6 H, d, J=2.3 Hz), 4.43 (0.4 H, d, J=2.3 Hz), 4.17-4.23 (1 H, m), 4.01 (0.45 H, d, J=1.8 Hz), 3.98 (0.55 H, d, J=1.8 Hz), 3.85-3.94 (1 H, m), 3.73 (1 H, dd, J=9.8, 5.3 Hz), 2.43-2.53 (1 H, m), 2.30-2.40 (1 H, m), 2.19-2.28 (1 H, m), 1.69-1.77 (1 H, m). LCMS (M+H) calcd for C14H19O2: 219.14; found: 219.05.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:30])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: COc1ccccc1C1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3.N1C2C(=CC=CC=2)[C:25]2([C:35]3=CC4OCOC=4[CH:42]=[C:34]3[O:33][CH2:32]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:42][C@H:34]1[CH2:35][CH2:25][CH2:32][O:33]1)[C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3
Reactant: O=C1Nc2c(Cl)cccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (98%) as a colorless solid: mp 192-193° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ7.23-7.18 (m, 1H), 7.08-6.98 (m, 2H), 6.53 (d, J=17.6 Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 4.80-4.69 (m, 2H), 4.53-4.47 (m, 2H), 4.20-4.11 (m, 1H), 3.95-3.60 (m, 4H), 2.99-2.93 (m, 2H), 2.04-1.59 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ177.7, 177.6, 161.1 (2C), 160.5, 160.3, 138.3, 138.0, 135.8, 135.4, 130.7, 130.6, 124.1, 122.7, 122.6, 120.5, 120.2, 119.9, 119.8, 119.2, 118.8, 114.3, 114.2, 92.4, 92.2, 80.0, 76.3, 76.1, 72.0, 72.0, 67.2, 66.9, 56.7, 56.5, 45.0, 44.9, 28.3, 28.2, 24.9, 24.9; MS (ES+) m/z 397.7 (M+1), 399.7 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH2:12])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: N#CC1(c2ncc(Br)cc2Cl)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: NCC1(c2ncc(Br)cc2Cl)CC1
Temperature: -78 °C
Reaction time: 72 h
Yield: 46.4 %

Procedure:
106 mg of 1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropanecarbonitrile (step 2) was dissolved in 2 ml of dichloromethane and was cooled down to −78° C. Then 0.91 ml of diisobutylaluminium hydride (1 M in tetrahydrofuran) was added dropwise. The reaction mixture was stirred at −78° C. for 1h, then at ambient temperature for three days. Then 0.40 ml of diisobutylaluminium hydride solution was added again at −78° C. and the reaction mixture was warmed to 40° C. and stirred for 24 hours. The reaction mixture was poured into a saturated solution of potassium sodium tartrate and the resulting mixture was stirred for 1 hour. The aqueous phase was extracted with three 25 ml portions dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. 140 mg of crude material was obtained as a yellow sticky solid. The residue was partitioned between 1N aqueous hydrochloric acid and ethyl acetate. The aqueous phase was adjusted to pH 14 by addition of an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. Thus, 50 mg of C-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropyl]-methylamine was obtained as a yellow sticky solid. 1H-NMR (CDCl3): 8.50 ppm (s, 1H), 7.83 ppm (s, 1H), 2.95 ppm (s, 2H), 1.40 ppm (s, 2H, broad), 0.99 ppm (m, 2H), 0.90 ppm (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Br)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Br)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
4′-Bromo-N-methyl-p-toluenesulfonanilide (0.90 g (2.65 mmol)) was dissolved in 5.0 ml of acetic acid. To this, 97% fuming nitric acid (0.64 ml (15.0 mmol)) was added dropwise, and the mixture was heated at 100° C. for 1.5 hours with stirring, followed by cooling to room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.64 g (63%) of the title compound as pale yellow crystals.