Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]2([OH:13])[CH2:12][CH2:11][N:10]([CH2:22][CH3:23])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(Cl)c2F)CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cccc(Cl)c2F)C1
Temperature: 120 °C

Procedure:
In a sealed tube a mixture of 3-(3-chloro-2-fluorophenyl)pyrrolidin-3-ol (0.5 g, 2.32 mmol), acetonitrile (3 mL), potassium carbonate (0.48 g, 3.48 mmol) and iodoethane (0.36 g, 2.32 mmol) was heated under microwave irradiation at 120° C. for 20 minutes. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4) and evaporated. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound. The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether (0.249 g). M.p. 142-145.5° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 24), 228 (19), 157 (15), 72 (27), 71 (bp).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[CH3:16][C:17]([CH3:19])=[O:18]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:17]([OH:18])([CH3:19])[CH3:16])[CH:7]=1
Reactant: COc1ccc(F)cc1Br
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a stirred solution of 2-bromo-4-fluoro anisole (4.1 g, 20 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under an atmosphere of argon was added n-butyl lithium (8.8 mL of 2.5 M solution in hexanes, 22 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with anhydrous acetone (5 mL). After 15 minutes, the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. Combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 2-(5-fluoro-2-methoxyphenyl)propan-2-ol as a light brown thick oil (85% yield) which solidified on standing. The crude product was used for the next reaction without further purification.
Reaction SMILES: Cl.[CH2:2]([S:4][CH2:5][CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.Cl[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(Cl)(Cl)Cl>[C:20]([O:19][C:17](=[O:18])[CH2:16][NH:7][CH2:6][CH2:5][S:4][CH2:2][CH3:3])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CCSCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCSCCNCC(=O)OC(C)(C)C
Yield: 34.2 %

Procedure:
To a solution of 10 g of 2-ethylthioethylamine hydrochloride and 15 g of triethylamine in 20 ml of chloroform was added with stirring 11 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an addition 1 hour. At the end of this period, the chloroform was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 5.3 g (34 percent) of N-(2-ethylthioethyl)glycine tert-butyl ester, B.P. 106°-9° C/1.5 mm Hg.
Reaction SMILES: [C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([CH:26]=O)=[C:23]([CH3:28])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:37][O:38][C:39](=[O:42])[CH2:40][NH2:41]>>[CH3:37][O:38][C:39](=[O:42])[CH2:40][NH:41][CH2:26][C:24]1[S:25][C:21]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:34])[CH3:35])[C:30]([CH3:31])([CH3:32])[CH3:33])=[C:11]([CH3:29])[CH:12]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:22][C:23]=1[CH3:28]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(C=O)s1
Agent: Cl
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(CNCC(=O)OC)s1
Yield: 63.9 %

Procedure:
Using a procedure analogous to Example 41, 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-carbaldehyde (additional example Lu-13-A) (2.11 g, 4.09 mm) and glycine methyl ester hydrochloride (0.56 g, 4.50 mmol) give the title compound (1.54 g, 2.61 mmol, 64%). %). 1H NMR (CDCl3), δ 0.06 (s, 3H), 0.12 (s, 3H), 0.70 (t, J=6.9 Hz, 6H), 0.91(s, 9H), 0.97 (s, 9H), 2.02-2.10 (m, 4H), 2.13 (s, 3H), 2.20 (s, 3H), 3.45 (s, 2H), 3.67 (dd, J=5.4, 3.4 Hz, 1H), 3.73 (s, 3H), 3.82-3.87 (m, 3H), 3.98 (dd, J=9.6, 3.4 Hz, 1H), 6.49 (s, 1H), 6.67 (d, J=8.3 Hz, 1H), 7.00-7.05 (m, 2H). LC/MS (m/z): calcd for C33H55NO4SSi (M)+: 589.9; found: 589.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]([CH:26]=O)[CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][N:21]3COCC[Si](C)(C)C)=[CH:13][CH:12]=1.N1CCCC1>C(O)C>[N:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]([CH:26]=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][NH:21]3)=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(-c3ccncc3)cc(C=O)cc21
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1cc(-c2ccncc2)c2cn[nH]c2c1
Temperature: 70 °C

Procedure:
To a solution of oxindole (12 mg, 0.08 mmol) and 4-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (31 mg, 0.087 mmol) in ethanol (2 mL) was added pyrrolidine (20 μL). The mixture was heated to 70° C. for 3 h. The solution was concentrated to dryness and treated with 4M HCl (1 mL) in ethanol (3 mL) at 70° C. for 4 h. The solution was cooled to rt and extracted with ethyl acetate (50 mL), dried over MgSO4 and concentrated to give the title compound as a mixture of E/Z isomers which were separated by preparatory HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH3:18])=[O:16])[CH:8]([CH3:19])[CH2:7][C:6]2=[O:20].[CH:21](OCC)=[O:22].[O-]CC.[Na+].[H-].[Na+]>C(O)C.C1C=CC=CC=1>[OH:22][CH:21]=[C:7]1[C:6](=[O:20])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([C:15]([O:17][CH3:18])=[O:16])[CH:8]1[CH3:19]
Reactant: COC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Reactant: CCOC=O
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: COC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate (13.8 g.) in 140 ml. of benzene containing 19 ml. of ethyl formate is added to sodium ethoxide freshly prepared from 4.8 g. of sodium hydride and 6 ml. of ethanol over a period of 45 min. After stirring at room temperature for 4 hrs. the reaction mixture is poured onto 250 ml. of ice-water. The aqueous layer is retained and the organic layer washed with 1N aqueous sodium hdyroxide. The washings are combined with the aqueous extracts and backwashed with benzene. The aqueous layer is then made acid with 12N hdyrochloric acid and extracted with chloroform. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is employed in subsequent reactions without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH2:2][C:3]1[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH:20]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)/C=C/c1ncccc1CBr
Product: CCOC(=O)/C=C/c1ncccc1Cc1cc2cc(Cl)ccc2[nH]1

Procedure:
The benzylic bromide of Step 2 (1.33 g; 4.91 mmol) was coupled with 5-chloroindole according to the procedure described in step 1 of example 2 to yield 1.22 g of the title compound.
Reaction SMILES: [H][H].[C:3]([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:11][C:10]2=[O:31])(=[O:5])[CH3:4]>[Pd].CO>[C:3]([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)([CH3:30])[CH2:11][C:10]2=[O:31])(=[O:5])[CH3:4]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(N)cc1)O2

Procedure:
Hydrogen gas was passed for 2 hours through a mixture of 3.6 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one, 1 g of 10% w/w palladium-on-carbon and 100 ml of methanol at room temperature under atmospheric pressure. The catalyst was then removed by filtration and the filtrate was condensed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a 2:1 by volume mixture of hexane and ethyl acetate, and the resulting crude product was recrystallized from acetone, to yield 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman-4-one. Its melting point was 177°-178° C.
Reaction SMILES: NC1SC(CC2C=CC=CC=2)=CC=1[C:7]([NH2:9])=[O:8].[NH2:17][C:18]1[S:19][C:20]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[C:28]1([CH:26]([C:20]2[S:19][C:18]([NH:17][C:7]([NH2:9])=[O:8])=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=2)[CH3:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(c1ccccc1)c1cc(C(N)=O)c(N)s1
Reactant: NC(=O)c1cc(Cc2ccccc2)sc1N
Product: CC(c1ccccc1)c1cc(C(N)=O)c(NC(N)=O)s1
Yield: 87 %

Procedure:
5-(1-Phenyl-ethyl)-2-ureido-thiophene-3-carboxylic acid amide was prepared by the same procedure as Example 6b except that 2-amino-5-benzyl-thiophene-3-carboxylic acid amide was replaced with 2-amino-5-(1-phenyl-ethyl)-thiophene-3-carboxylic acid amide to give the above titled compound as a light brown solid (87% yield). LC-MS [M+H]+ m/z 290.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C@H:15]2[O:19][C:18](=[O:20])[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:14])(=O)=O)=CC=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CO>[N:37]([CH2:12][C@@H:13]([C@H:15]1[O:19][C:18](=[O:20])[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[OH:14])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)[C@H]2OC(=O)C(OCc3ccccc3)=C2OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NC[C@H](O)[C@H]1OC(=O)C(OCc2ccccc2)=C1OCc1ccccc1

Procedure:
(R)-5-[2-(4-methylphenylsulfonyloxy)-(S)-1-hydroxyethyl]-3,4dibenzyloxy-5H-furan-2-one (5)† (550 mg, 1.1 mmol), sodium azide (190 mg, 1.7 mmol) and methanol (2 ml) were heated under reflux for 6 hours. The reaction mixture was cooled and most of the solvent removed by evaporation at room temperature. The resulting material was partitioned between water (25 ml) and dichloromethane (25 ml) and the aqueous phase extracted with dichloromethane (25 ml). The combined organic fractions were dried (MgSO4), filtered and volatile components evaporated under reduced pressure (8 mm/Hg) at room temperature to give the product (6) as a yellow waxy solid (375 mg, 89%). This material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH:10](OCC)=[O:11]>C(OCC)C>[CH3:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][CH:10]=[O:11])[CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1cccc(C)c1
Reactant: CCOC=O
Solvent: CCOCC
Product: Cc1cccc(C#CC=O)c1
Temperature: -70 °C
Yield: 47 %

Procedure:
1.56 g of 3-ethynyltoluene was dissolved in 20 ml of ethyl ether, and with stirring at -70° C., 8.5 ml of 1.5M n-butyllithium-hexane solution and 1.2 ml of ethyl formate were added. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice water, and the organic layer was separated. The solvent was evaporated to give 900 mg (yield 47%) of 3-(3-methylphenyl)-2-propynaldehyde as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([O:32][CH2:33][CH3:34])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH2:16][N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.[Mg].N>CO.BrCCBr>[CH3:1][O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([CH2:16][N:17]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15]2)=[CH:11][CH:12]=1
Reactant: CCCCCCCN(CC1(c2ccc(C=C(OCC)C(=O)OCC)cc2)CC1)C(=O)OC(C)(C)C
Agent: N
Agent: [Mg]
Solvent: CO
Solvent: BrCCBr
Product: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 3-(4-{1-[(tert-butoxycarbonyl-heptyl-amino)-methyl]-cyclopropyl}-phenyl)-2-ethoxy-acrylic acid ethyl ester (680 mg, 1.40 mmol) in anhydrous methanol (20 mL) in a flame dried round bottom flask under an nitrogen atmosphere was added magnesium turnings (53.50 mmol, 85 mg). After 30 min, 1,2-dibromoethane (1 drop) was added directly to the magnesium turnings via pipette, initiating H2 gas evolution from the magnesium. At this time a dry stir bar was added and the mixture was stirred at room temperature until all of the magnesium solid had dissolved. Two additional portions of magnesium (80 mg) were added and allowed to dissolve (16 h). The mixture was poured over 25 mL of ice cooled 2NHCl. The acidic mixture was brought to pH 8.5 by the addition of concentrated aqueous ammonia, then was extracted with diethyl ether (3×). The organic layers were combined, washed with saturated NaCl (3×), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-(4-{1-[(tert-butoxycarbonyl-heptyl-amino)-methyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester as a clear oil (580 mg, 87%).
Reaction SMILES: C(O[Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[CH:14]1([Mg]Cl)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>C(OCC)C>[CH:14]1([Si:4]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)C1CCCCC1
Reaction time: 6 h

Procedure:
60 ml of dry diethyl ether and 14.0 gram (0.067 mole) of tetraethoxysilane were charged in a 250 ml flask equipped with a reflux condenser and a stirring apparatus in an atmosphere of nitrogen and above prepared solution of cyclohexyl magnesium chloride was slowly added while keeping the internal temperature below 10° C. After completion of addition stirring was carried out at room temperature for 6 hours and at reflux temperature for 2 hours. To the resulting reaction mass 10-20 ml of saturated aqueous ammonium chloride solution was added drop wise to dissolve magnesium salt. The organic layer was separated from the aqueous layer, dried and evaporated to give crude cyclohexyltriethoxysilane. This crude was purified by fractional distillation under reduced pressure, yielding 14.2 gram of pure cyclohexyltriethoxysilane (86% of the theoretical maximum yield based on the amount of tetraethoxysilane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Li]CCCC.[C:17](=[O:19])=[O:18].O>C1COCC1>[F:11][C:9]1[CH:10]=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[CH:5]2
Reactant: O=C=O
Reactant: Fc1cc(Br)cc2cc[nH]c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(F)c2[nH]ccc2c1
Reaction time: 4 h

Procedure:
To a solution of 5-bromo-7-fluoroindole 70f (1.71 mmol, 365 mg) in THF at −60° C. was added n-BuLi (1.6 M solution in hexanes, 5.2 mmol, 3.2 mL). The solution was kept at −60° C. for 4 h and was then poured onto an excess of freshly crushed dry ice. Water was added and the mixture was acidified to pH=4. The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to give compound 70h.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4]C[CH2:2]1.[O:23]=[S:24]1(=[O:30])CCC(N)C1>>[O:23]=[S:24]1(=[O:30])[CH2:4][CH2:5][CH:1]([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:2]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCS(=O)(=O)C1
Product: Cc1nc(NCc2ccccn2)nc(NC2CCS(=O)(=O)C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (1,1-dioxidotetrahydro-3-thienyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.91 (s, 3H), 2.22 (m, 1H), 2.29 (s, 3H), 2.20-2.26 (m, 1H), 2.80-2.91 (m, 1H), 2.95 (bs, 1H), 3.05-3.15 (m, 1H), 3.18-3.24 (m, 1H), 4.69 (bs, 2H), 4.80-4.89 (m, 2H), 5.92 (bs, 1H), 7.17 (t, J=3.9 Hz, 1H), 7.34 (d, J=5.8 Hz, 1H), 7.64 (t, J=6.4 Hz, 1H), 8.57 (d, J=2.8 Hz, 1H); MS (ESI) m/z 348.8 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7]2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([N:1]1[CH2:6][CH2:5][C:4]2([C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)COC21CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)N1CCC2(CC1)OCc1ccccc12
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
3H-spiro[2-benzofuran-1,4′-piperidine] (5 g, 26 mmol) was dissolved in THF (100 mL) and cooled in ice. Then N-ethyldiisopropylamine (4.94 mL, 29 mmol) and chloroacetyl chloride (2.31 mL, 29 mmol) were added. The mixture was stirred at 20° C. for 15 min. The solid was filtered off and washed with THF. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica gel with heptane/AcOEt 70:30. One obtained light yellow crystals (6.5 g, 92%). MS: m/z=266 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(CN2CCCCCC2)cc1
Agent: Cl
Product: COc1cc(NCCCc2ccc(CN3CCCCCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 72.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (416 mg) and 4-azepan-1-ylmethylbenzoic acid hydrochloride (328 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337, the title compound (386 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]([NH2:23])[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=1.[O:24]([CH2:28][CH:29]=O)[CH2:25][CH:26]=O.O.[BH3-]C#N.[Na+].Cl>CC#N>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]([N:23]2[CH2:29][CH2:28][O:24][CH2:25][CH2:26]2)[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=CCOCC=O
Reactant: COc1cccc(C(N)C(c2cccnc2)c2cccnc2)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(C(C(c2cccnc2)c2cccnc2)N2CCOCC2)n1

Procedure:
To a solution of 1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethanamine (75 mg, 0.25 mmole) in CH3CN (1 mL) was added a solution of 2,2′-oxydiacetaldehyde in H2O (1.47 mL, 0.5 M, 0.73 mmole). After 10 minutes NaBH3CN (92 mg, 1.47 mmole) was added. After 2 hr 1N HCl (2 mL) was added.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C([N:15](CC)CC)C.C(OC(Cl)=O)C(C)C.N>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:15])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(N)=O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzoic acid (400 mg, 2.4 mmol) and triethylamine (560 μl, 3.5 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was added isobutylchloroformate (320 μl, 2.4 mmol), and the mixture was stirred at 0° C. for 1 hour. The solution was warmed to room temperature and was saturated with ammonia gas, then stirred for 15 hours at room temperature. The mixture was diluted with ethyl acetate, then washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, and brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded 280 mg, 1.7 mmol (70%) of 3-fluoro-4-(methyloxy)benzamide. MS (EI) for C8H8FNO2: 170 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-bromobenzoic acid (3.30 g, 16.4 mmol) in anhydrous DCM (120 mL) was added oxalyl chloride (6.26 g, 49.3 mmol) dropwise at 0° C. followed by 3 drops of DMF. The resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated in vacuo to give 4-bromobenzoyl chloride as a yellow solid. The solid was dissolved in anhydrous THF (40 mL) and a solution of Preparation 3 tert-butyl (3R)-3-(isoquinolin-1-ylamino)piperidine-1-carboxylate (4.89 g, 14.9 mmol) in anhydrous THF (50 mL) was added. The resulting solution was treated with lithium bis(trimethylsilyl)amide (44.8 mL, 44.8 mmol, 1 M) dropwise at 0° C. The reaction mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a gradient of (0-25%) EtOAc/petroleum ether to afford the title compound (4.80 g, 63%) as a yellow solid.