Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[CH3:14][C:15]1[CH:16]=[C:17]([P:22]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=2)Cl)[CH:18]=[C:19]([CH3:21])[CH:20]=1>C1COCC1.CC(OC)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:22]([C:24]1[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: Cc1cc(C)cc(P(Cl)c2cc(C)cc(C)c2)c1
Reactant: Brc1ccccc1I
Agent: CC(C)[Mg]Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccccc2Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 9.67 g (34.2 mmol) of 1-bromo-2-iodobenzene in 30 ml of THF are added dropwise, at −78° C., 17.6 ml (37.6 mmol) of an isopropylmagnesium chloride solution (2 molar in THF). The mixture is stirred at a temperature between −30° C. and −40° C. for a further 1 hour, then cooled again to −78° C., and a suspension of 10.4 g (37.6 mmol) of bis(3,5-dimethylphenyl)chlorophosphine in 10 ml of THF and 10 ml of TBME are added. The cooling is removed and the reaction mixture is stirred at room temperature overnight. The resulting solution is admixed with 50 ml of water and extracted with water/TBME. The organic phases are collected and dried over sodium sulphate, and the solvent is distilled off under reduced pressure on a rotary evaporator. The solid white crude product is purified by chromatography (silica gel 60; eluent=methylene chloride). The desired product is obtained as a white solid in a yield of 56%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[C:30]([C:34]1[C:39]([F:40])=[C:38]([S:41][CH3:42])[N:37]=[C:36](Cl)[N:35]=1)([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:30]([C:34]1[C:39]([F:40])=[C:38]([S:41][CH3:42])[N:37]=[C:36]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[N:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CSc1nc(Cl)nc(C(C)(C)C)c1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
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: COCCOC
Product: CSc1nc(-c2c[nH]c3ncc(Cl)cc23)nc(C(C)(C)C)c1F
Temperature: 150 °C
Yield: 26.8 %

Procedure:
To a degassed solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.22 g, 0.50 mmol), 4-tert-butyl-2-chloro-5-fluoro-6-thiomethoxypyrimidine, 40a, (0.12 g, 0.50 mmol) in 1,2-dimethoxyethane (3 mL) and aqueous Na2CO3 (0.75 mL of 2 M solution, 1.5 mmol) was added tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.03 mmol). The reaction mixture was degassed for an additional 15 minutes. The mixture was heated in a microwave at 150° C. for 20 minutes. Ethyl acetate (15 mL) was added. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0%-100% EtOAc/hexanes) to afford the desired product, 40b (47 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=[CH:10][C:2]1=2.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][NH2:21]>>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([CH2:11][NH:12][C:3](=[O:4])[C:2]([NH:21][CH2:20][CH2:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)=[O:1])=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: NCCc1ccccn1
Reactant: NCc1cccc2c1OCCO2
Product: O=C(NCCc1ccccn1)C(=O)NCc1cccc2c1OCCO2
Yield: 50 %

Procedure:
Prepared in a similar manner to example 122 using (2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanamine, ethyl oxalyl chloride, and 2-(2-pyridinyl)ethyl amine; yield 50%; m/e=342 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=[O:21])=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[OH:21])=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCc3ccc(Br)cc32)cc1
Temperature: 25 °C

Procedure:
6.4 ml (6.4 mmol) of a solution of 4-methoxyphenylmagnesium bromide in tetrahydrofuran (1M soln) are added dropwise to a solution of 0.9 g (4.26 mmol) of 6-bromo-1-indanone in 10 ml of absolute tetrahydrofuran under nitrogen at −20° C. The reaction solution is subsequently warmed to room temperature over the course of 12 hours, then 45 ml of 10% ammonium chloride solution are added, and finally the mixture is extracted twice with 20 ml of methylene chloride each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography on silica gel (petroleum ether/ethyl acetate 4:1), giving 1.1 g of 6-bromo-1-(4-methoxyphenyl)indan-1-ol as pale-yellow oil. LC/MS: 302 (M+H-18 (water)). This oil is then dissolved in 20 ml of methylene chloride, the solution is cooled to −20° C., and, after addition of 0.8 ml (5 mmol) of triethylsilane, 0.53 ml (4.2 mmol) of boron trifluoride/diethyl ether complex is added. The reaction solution is subsequently warmed to room temperature, stirred at room temperature for four hours and then washed successively with 20 ml of saturated sodium hydrogencarbonate solution and 20 ml of saturated sodium chloride solution. After the methylene chloride solution has been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography on silica gel (petroleum ether/ethyl acetate 95:5), giving 0.52 g of 6-bromo-1-(4-methoxyphenyl)indane as colourless oil; 1H-NMR (d6-DMSO): δ 7.34 ppm (d, 1H, J=7.9 Hz), 7.26 ppm (d, 1H, J=7.9 Hz), 7.11 ppm (d, 2H, J=8.97 Hz), 6.93 ppm (s, 1H), 6.90 ppm (d, 2H, J=8.97 Hz), 4.31 ppm (t, 1H, J=8.27 Hz), 3.74 ppm (s, 3H, OCH3), 2.98 ppm (m, 1H), 2.85 ppm (m, 1H), 2.48 ppm (m, 1H), 2.0 ppm (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH2:26])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([OH:45])[CH2:43]Br)=[CH:38][C:37]=1[NH:46][CH:47]=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:43][C@@H:42]([C:39]2[CH:40]=[CH:41][C:36]([O:35][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:37]([NH:46][CH:47]=[O:48])[CH:38]=2)[OH:45])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 25 °C

Procedure:
A suspension composed of compound 26 (0.59 g, 1.60 mmol), compound 5 (0.42 g, 1.19 mmol); K2CO3 (0.23 g, 1.68 mmol) and chloroform (25 mL) was heated to reflux for 72 h, then cooled to ambient temperature. The solid was vacuum filtered and washed with chloroform (3×10 mL). The filtrate and the washings were combined and concentrated. The residue was subjected to column chromatography eluting with 0-10% methanol in dichloromethane. The un-reacted starting material 26 (0.39 g; 66% recovery) was recovered in the separation. A mixture of two diastereomers of the desired products 27, which were not separable in this step, was obtained (0.29 g, 28%) as a colorless, viscous oil: 1H NMR (500 MHz, CDCl3) δ 1.08 (d, 3H), 1.37 (m, 2H), 1.48-1.68 (m, 6H), 2.55 (m, 4H), 2.74 (br, 2H), 2.92 (m, 1H), 3.18 (m, 2H), 3.58 (m, 1H), 3.72 (m, 1H), 4.70 (m, 1H), 4.80 (br, 1H), 5.08 (m, 4H), 6.92 (m, 1H), 7.08 (m, 5H), 7.22 (t, 1H), 7.34 (m, 10H), 7.92 (s, 1H), 8.31 (s, 1H); m/z (ESI) 638 [C39H47N3O5+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:17][S:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:15])=[O:16]
Reactant: COC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)CCCCC1(C(=O)O)CCCC1
Temperature: 52.5 °C
Yield: 92.3 %

Procedure:
To a solution of 1-[4-(methylsulfonyl)butyl]cyclopentane carboxylic acid methyl ester (18.8 mmol, 4.94 g) in a mixture of THF (38 mL) and methanol (38 mL) was added 1 N sodium hydroxide (38 mL). The mixture was heated to 50-55° C. for 15 h at which point TLC analysis of the reaction mixture indicated the absence of starting material and the mixture was allowed to cool to room temperature. The solvent was removed under vacuum and the residue was diluted with water (100 mL) and extracted with ether (2×50 mL) to remove any neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2×75 mL). The combined extracts were washed with brine solution and dried over anhydrous sodium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was dried under high vacuum to afford 4.31 g (92%) of the title compound as a low melting white solid. LR MS (C11H20O4S): 249 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]3[CH2:20][CH2:19]3)[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]3[CH2:20][CH2:19]3)[C:11]3[N:12]([C:14]([C:22]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnc3c(C4CC4)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-cyclopropyl-3-iodo-imidazo[1,2-a]pyridine (example C.27 step 5) (592 mg, 2 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (230 mg, 2 mmol) according to general procedure II. Obtained as a yellow solid (128 mg, 22%). MS (ISP) 385.2 [(M+H)+], 387 [(M+2+H)+]; mp 246° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([O:11][S:12](=[O:33])(=[O:32])[NH:13][C:14](=[O:31])[CH2:15][C:16]2[C:21]([CH:22]([CH3:24])[CH3:23])=[CH:20][C:19]([CH:25]([CH3:27])[CH3:26])=[CH:18][C:17]=2[CH:28]([CH3:30])[CH3:29])=[C:4]([CH:34]([CH3:36])[CH3:35])[CH:3]=1.[C:37](O)(=[O:39])[CH3:38].O>>[OH:39][CH2:37][CH2:38][NH:1][C:2]1[CH:3]=[C:4]([CH:34]([CH3:36])[CH3:35])[C:5]([O:11][S:12](=[O:33])(=[O:32])[NH:13][C:14](=[O:31])[CH2:15][C:16]2[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:18][C:19]([CH:25]([CH3:26])[CH3:27])=[CH:20][C:21]=2[CH:22]([CH3:23])[CH3:24])=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)O
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(N)cc2C(C)C)c(C(C)C)c1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(NCCO)cc2C(C)C)c(C(C)C)c1
Reaction time: 8 h

Procedure:
[(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 4-amino-2,6-diisopropyl-phenyl ester (1.0 g, 1.9 mmol) was suspended in 50 mL of 1:1 glacial acetic acid/water and a stream of ethylene oxide was bubbled in for 15 minutes. The reaction mixture was sealed and allowed to stir overnight. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. Dried the organic layer over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.07 g of the title compound as a tan solid; mp 149-152° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]4[N:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]3[C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([C:36]3([NH:40]C(=O)OC(C)(C)C)[CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[ClH:48].O1CCOCC1>C(Cl)Cl>[ClH:48].[ClH:48].[ClH:48].[NH2:40][C:36]1([C:33]2[CH:32]=[CH:31][C:30]([C:29]3[N:15]4[C:16]5[CH:28]=[CH:27][CH:26]=[N:25][C:17]=5[NH:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:14]4=[N:13][C:12]=3[C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=3)=[CH:35][CH:34]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NS(C)(=O)=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 77.9 %

Procedure:
tert-Butyl {1-[4-(2-{4-[(methylsulfonyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (30.9 mg, 0.0476 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 13.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (24.4 mg, 77.9%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 9.90 (s, 1H), 8.76 (br s, 2H), 8.67 (s, 1H), 8.12 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=8.0, 1.6 Hz, 1H), 7.59-7.53 (m, 2H), 7.49-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.36-7.29 (m, 3H), 7.18-7.11 (m, 3H), 6.90 (dd, J=8.0, 1.6 Hz, 1H), 6.76 (dd, J=8.0, 4.8 Hz, 1H), 3.02 (s, 3H), 2.62-2.53 (m, 4H), 2.27-2.13 (m, 1H), 1.88-1.75 (m, 1H); LCMS: 549 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:19][C:20]2[N:21]([CH3:31])[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2F)[CH:6]=[CH:7][CH:8]=1)[CH3:2].C(C1C=CC([F:54])=C(C(C2N(C)N=C(C3C=CC=CC=3)N=2)O)C=1)C>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:54])=[C:5]([N:9]([CH2:19][C:20]2[N:21]([CH3:31])[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[C:10]2[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cccc(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)cc2F)c1
Reactant: CCc1ccc(F)c(C(O)c2nc(-c3ccccc3)nn2C)c1
Product: CCc1ccc(F)c(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)cc2)c1

Procedure:
Following the procedure for Intermediate 382.1, Intermediate 385.1 (150 mg, 0.48 mmol) gave 155 mg of Intermediate 385.2 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.95 (t, J=7.58 Hz, 3H) 2.35 (q, J=7.58 Hz, 2H) 3.59 (s, 3H) 5.87 (d, J=6.11 Hz, 1H) 6.35 (d, J=5.87 Hz, 1H) 6.48-6.57 (m, 2H) 6.86-6.94 (m, 1H) 6.95-7.02 (m, 1H) 7.11-7.19 (m, 1H) 7.22-7.32 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.CN([CH:28]=[O:29])C>>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([CH:28]=[O:29])=[CH:3][CH:4]=3)[CH2:13][CH2:14]1
Reactant: Brc1ccc2ncc(N3CCOCC3)nc2c1
Reactant: CN(C)C=O
Agent: CC[SiH](CC)CC
Product: O=Cc1ccc2ncc(N3CCOCC3)nc2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To a solution of 4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 0.2 mol, 1.0 eq.) in DMF (500 mL) was added TEA (139 mL, 1.0 mol, 5.0 eq.), Et3SiH (127 mL, 0.8 mol, 4.0 eq) and Pd(dppf)Cl2CH2Cl2 (8.16 g, 0.01 mol, 0.05 eq.). The resulting mixture was stirred at 90° C. for 12 h in an autoclave under CO (1 MPa), then cooled and concentrated. The resulting residue was purified by flash column chromatography (EA/PE=1/1) to afford 3-morpholinoquinoxaline-6-carbaldehyde as a yellow solid (40 g, 82.3%).
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:32]>CO>[ClH:32].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-tetradecylpropane (1.25 g) was dissolved in 100 ml of methanol and 19.4 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane=1:1 in order to give 791 mg of 2-amino-2-tetradecyl-1,3-propanediol hydrochloride.
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[C:23]1([CH2:29][C:30](N)=[NH:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N>C(O)C.CCOCC>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[O:1]([CH:8]([CH3:11])[CH2:9][NH:10][C:30](=[NH:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: CC(CN)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CCOCC
Solvent: CCO
Product: CC(CNC(=N)Cc1ccccc1)Oc1ccccc1

Procedure:
2-Phenoxypropylamine (6.0 g.) was added to a suspension of phenylacetamidine p-toluenesulphonate (12.4 g.) in absolute ethanol (20 ml.). The mixture was heated to reflux for 4 hours by which time the initially vigorous evolution of ammonia had practically ceased. The resulting solution was cooled somewhat and diluted with ether to give an oil which rapidly crystallised on scratching. The solid was filtered and recrystallised from a mixture of ethanol and water to give N-(2-phenoxypropyl)phenylacetamidine p-toluenesulphonate, m.p. 127°-129°.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1oc(Br)cc1C=O
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: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C=O)c(C)o2)cn1
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.5 g), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 82%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[O:13]C.O>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[OH:13]
Reactant: COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)c(O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
56 g of 4-(2,4-dichlorophenoxy)-3-methoxybenzonitrile are dissolved in 120 ml of dichloromethane. At 0°, a 1M solution of borontribromide in dichloromethane is added slowly in 4 portions of 6 ml each. The reaction mixture is then stirred for 2 days at room temperature. After renewed cooling to 0°, water is added carefully until no reaction is observed any more. The reaction mixture is then washed with water, a saturated aqueous solution of sodium bicarbonate and finally with brine. The organic phase is dried over magnesium sulfate and evaporated under vacuum. The residue is recrystallized from ether/hexane to yield 4-(2,4-dichlorophenoxy)-3-hydroxybenzonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][C:8]([C:15](=O)[CH3:16])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[C:5]([CH:18]([CH3:20])[CH3:19])=[CH:4][CH2:3]1.[CH3:22][CH2:23][O:24][C:25]([CH:27](P(OCC)(OCC)=O)[F:28])=[O:26].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[F:28]/[C:27](=[C:15](/[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:1])([CH3:21])[CH2:3][CH:4]=[C:5]2[CH:18]([CH3:19])[CH3:20])=[CH:10][C:9]=1[O:12][CH2:13][CH3:14])\[CH3:16])/[C:25]([O:24][CH2:23][CH3:22])=[O:26]
Reactant: CCOc1cc2c(cc1C(C)=O)C(C(C)C)=CCC2(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4,4-dimethyl-6-ethoxy-1-isopropyl-3,4-dihydronaphthalen-7-yl)ethanone (Compound A-24, 240 mg, 0.840 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.51 mL, 2.52 mmol) were reacted with lithium diisopropylamide (2.60 mmol) in THF (2 mL) to produce the title compound after purification by flash column chromatography (silica gel, 97:3 hexane/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10](=O)[CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Cl.[CH3:25][O:26][NH2:27].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:10](=[N:27][O:26][CH3:25])[CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cnc(C(=O)CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(OC)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
To a solution of 120 mg of N-[2-(3-chloro-5-methoxypyridin-2-yl)-2-oxoethyl]phthalimide and 60 mg of methoxyamine hydrochloride in 5 ml of ethanol, 85 mg of pyridine was added, and the mixture was stirred at 80° C. for 6 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 101 mg of the desired product as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13]>C(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:12](=[O:13])[N:11]([CH3:10])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
To a solution of 4-hydroxymethylphenol (10 mmol) and 4-diazabicyclo[2.2.2]octane (DABCO) (10 mmol) in CH2Cl2 (30 mL) was added N-methyl-N-phenylcarbamoyl chloride (10 mmol). The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with 1M aqueous HCl and brine. The organic phase was dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 EtOAc-Heptane 1:1) to give 2.18 g (85%) of the title compound as an oil.