Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl[C:44]([O:46][CH3:47])=[O:45].[CH3:48][Si:49]([CH3:58])([CH3:57])[C:50]1[O:54][CH:53]=[C:52]([CH:55]=O)[CH:51]=1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:48][Si:49]([CH3:58])([CH3:57])[C:50]1[O:54][CH:53]=[C:52](/[CH:55]=[C:12](/[C:44]([O:46][CH3:47])=[O:45])\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:51]=1
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC/C(=C\c1coc([Si](C)(C)C)c1)C(=O)OC
Reaction time: 1 h

Procedure:
Potassium bis(trimethylsilyl)amide (a 0.5 M solution in toluene; 14.5 ml, 7.24 mmol) was added to a solution of dodecyltriphenylphosphonium bromide (1.82 g, 3.56 mmol) in tetrahydrofuran (10 ml) at -78° under argon. After one hour, methyl chloroformate (0.28 ml, 3.56 mmol) was added, followed by 5-trimethylsilyl-3-furaldehyde (300 mg, 1.78 mmol) after one hour. Stirring was continued overnight while the cooling bath attained room temperature. The mixture was quenched with methanol/water (30 ml, 1:1). Extraction (ethyl ether/hexane, 1:1) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was flash chromatographed on silica using 20% ethyl ether/hexane. The title ester was obtained as a pale yellow oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) in dichloromethane (1.5 ml) was added at room temperature triethylamine (88.7 mg, 122 μl, 0.876 mmol) and methanesulfonyl chloride (43 mg, 29.2 μl, 376 μmol). The mixture was allowed to stir at room temperature for 18 h, and was afterwards evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as a white solid (62 mg, 61%), MS (ISP) m/z=405.4 [(M+H)+], mp 142° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:15][CH2:16][CH3:17])=O.[OH-].[K+]>C1COCC1.C(O)C.O>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH:16]([OH:15])[CH2:17][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC/C=C\CCCBr
Reactant: CCOC=O
Agent: [K+]
Agent: [Mg]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCCC/C=C\CCCC(O)CCC/C=C\CCCCC
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a suspension of magnesium turnings (1.4 g, 55.1 mmol) in anhydrous THF (6 mL) under nitrogen was slowly added a solution of (Z)-1-bromodec-4-ene 3 (11.5 g, 52.5 mmol) in THF (12 mL). The reaction mixture was stirred at 45° C. for 30 minutes under nitrogen. The solution was cooled to 0° C. and a solution of ethyl formate (4.1 g, 55.1 mmol) in THF (12 mL) was added dropwise to over 5 minutes. The solution was stirred at room temperature for 2 hours then cooled to −15° C. and quenched slowly with water (10 mL) followed by 5M hydrochloric acid (15 mL). Once the magnesium had completely dissolved, the solution was diluted with water (50 mL) and extracted with hexanes (3×75 mL). The combined extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue obtained was dissolved in ethanol (40 mL) and a solution of potassium hydroxide (4.4 g, 78.7 mmol)) in water (10 mL) was added. The reaction mixture was stirred vigorously for 30 minutes then concentrated in vacuo to remove ethanol. The solution was then made acidic with 5M hydrochloric acid (15 mL) and extracted with hexanes (3×75 mL). The combined hexanes extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The crude product was purified by column chromatography (100% hexanes to 2.5% ethyl acetate in hexanes) to afford (6Z,15Z)-henicosa-6,15-dien-11-ol 4 as a pale yellow oil (5.6 g, 35%). Rf 0.4 (10% EtOAc-Hexanes).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].C(=O)(O)[O-].[Na+]>ClCCl.CO>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:20](=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (22.3 mL, 0.160 mmol) was added with stirring to a solution of 3-amino-4-chloroquinoline, see Surrey et al., Journal of the American Chemical Society, 73, pp. 2413-2416 (1951), (13.2 g, 74.0 mmol) in anhydrous dichloromethane (100 mL). A solution of butyryl chloride (13 mL, 125 mmol) in dichloromethane (50 mL) was then added dropwise, and the reaction mixture was stirred at ambient temperature overnight. Methanol (25 mL) was added, and the reaction mixture was stirred for one hour at ambient temperature. Saturated aqueous sodium bicarbonate (50 mL) was added, and the resulting mixture was stirred at ambient temperature for 30 minutes and then allowed to stand. The aqueous layer was separated and extracted with dichloromethane (75 mL), and the combined organic fractions were then washed with saturated aqueous sodium bicarbonate (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product (22.8 g) was recrystallized from a mixture of toluene (45 mL) and hexane (15 mL) to provide 9.2 of N-(4-chloroquinolin-3-yl)butanamide as brown needles.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]#[N:54])[N:44]2[C:43]1=[O:55]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]#[N:54])[N:44]2[C:43]1=[O:55])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C#N)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (11 mg, 0.020 mmol) and Intermediate 36 (5.3 mg, 0.020 mmol) to give a white solid (4.7 mg, 31% yield). Anal. Calcd. for C43H51N5O5S m/z 749.7. found: 750.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.22 (6H, m), 7.22-7.11 (6H, m), 7.08 (2H, d, J=6.0 Hz), 6.96 (2H, d), 5.36 (1H, d, J=3.8 Hz), 5.24 (1H, d, J=4.9 Hz), 5.07-4.90 (1H, m), 4.89-4.74 (1H, m), 4.02-3.86 (1H, m), 3.79 (3H, s), 3.50-3.32 (1H, m), 3.07-2.60 (5H, m), 2.57-2.35 (2H, m), 2.15 (2H, t, J=13.2 Hz), 2.05-1.87 (3H, m), 1.85-1.62 (8H, m), 1.62-1.06 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.O[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][C:31]5=[O:36])=[C:19]([O:24][CH3:25])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1COCCN1CCO
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCOCC1=O
Temperature: 80 °C
Yield: 42.9 %

Procedure:
Combine 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.70 g, 1.82 mmol), 4-(2-hydroxy-ethyl)-morpholin-3-one (0.50 g, 3.45 mmol) and triphenylphosphine (0.50 g, 1.90 mmol) in THF (10.0 mL), stir for 10 min and add DIAD (0.77 g, 3.81 mmol). Heat to 80° C. for 2 days, cool the reaction mixture, and dilute with water. Extract with CH2Cl2 (2×), combine the organics, dry, and concentrate under vacuum. Purify the product by flash chromatography using 0-10% MeOH in CH2Cl2 to give the title compound (0.40 g, 43%). MS (ES+) 512.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, 2H, J=8.6 Hz), 7.47 (d, 2H, J=8.6 Hz), 7.40 (d, 1H, J=7.5 Hz), 6.98-6.95 (m, 3H), 6.91 (dd, 1H, J=8.6, 2.4 Hz), 4.27 (t, 2H, J=5.2 Hz), 4.17 (s, 2H), 3.89-3.81 (m, 7H), 3.68 (t, 2H, J=5.1 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.[CH3:39][NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1>CC(N(C)C)=O>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:40]([CH3:39])[CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: CNCCN1CCN(C)CC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 67.4 %

Procedure:
DIPEA (0.105 mL, 0.60 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 0.207 g, 0.5 mmol) and N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (Intermediate 109, 0.079 g, 0.50 mmol) in DMA (5 mL). The mixture was heated in a microwave at 140° C. for 3 h. An additional portion of N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (8 mg, 0.05 mmol) was added and the mixture was heated in a microwave at 140° C. for a further 1 h before being cooled to r.t. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. Purification by ion exchange chromatography, using an SCX column and eluting with 1M methanolic ammonia provided crude material after concentration of appropriate fractions in vacuo. Further purification by FCC, eluting with 2-8% CH3OH in CH2Cl2 gave the title compound (0.186 g, 67%) as an orange foam; 1H NMR: (CDCl3) 2.26 (3H, s), 2.32-2.45 (4H, m), 2.45-2.57 (4H, m), 2.61 (2H, t), 2.89 (3H, s), 3.29 (2H, t), 3.98 (3H, s), 6.65 (1H, s), 6.93-7.00 (1H, m), 7.38 (1H, ddd), 7.44 (1H, s), 8.40 (1H, s), 8.49 (1H, d), 8.55 (1H, d), 8.91 (2H, d); m/z: ES+ MH+ 552.59.
Reaction SMILES: C(O)CO.[CH2:5]([O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH:30]3[CH2:32][CH2:31]3)[CH:20]=2)=[C:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])[C:16]([C:41]([O:43]CC)=O)=[C:15]1[CH:46]=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:49][NH2:50]>O>[CH2:5]([O:12][CH2:13][N:14]1[C:15]2[CH:46]=[N:49][NH:50][C:41](=[O:43])[C:16]=2[C:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])=[C:18]1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:27])[F:28])=[C:21]([O:29][CH:30]2[CH2:32][CH2:31]2)[CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1c(Cc2ccccc2F)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Solvent: OCCO
Solvent: O
Product: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Temperature: 130 °C
Reaction time: 8.5 h
Yield: 90.3 %

Procedure:
To 46 ml of ethylene glycol solution containing 5.01 g (8.44 mmol) of ethyl 1-benzyloxymethyl-5-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4-(2-fluorobenzyl)-2-formyl-1H-pyrrol-3-carboxylate obtained in the following Reference example 36-(f) was added 2.13 ml (42.5 mmol) of hydrazine monohydrate at 60° C., and then the mixture was stirred at 130° C. for 8.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1→1:2 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 4.28 g of the title compound as a white solid. (Yield: 90%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28]#[N:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCCl>[CH2:15]([N:22]1[C:26]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:25][CH:24]=[C:23]1[CH2:27][C:28]#[N:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N#CCc1cccn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 8.43 ml. (0.0663 mole) of p-chlorobenzoyl chloride and 8.8 g. (0.0663 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane is added to a solution of 13.0 g. (0.0663 mole) of 1-benzylpyrrole-2-acetonitrile in 50 ml. of 1,2-dichloroethane at 5° C. over a 5 minute period. The mixture is stirred for 15 minutes, and then heated quickly to reflux for 3 minutes. The reaction mixture is poured into ice-hydrochloric acid and then filtered. The aqueous layer is separated and washed with chloroform. The combined organic solutions are washed successively with N,N-dimethylaminopropylamine solution, dilute hydrochloric acid, and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the oily residue dissolved in benzene-methylcyclohexane and seeded with crystals of 1-benzyl-4-(p-chlorobenzoyl)-pyrrole-2-acetonitrile. After crystallization of the latter substance is complete, the mother liquor is filtered and evaporated and the residue crystallized from methanol. The crystals thus obtained are recrystallized from methanol to give l-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile as a yellow solid, m.p. 104-106° C.
Reaction SMILES: ClC[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](OC(C)(C)C)=O)=[O:4].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:6]1[NH:5][C:3](=[O:4])[CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:7]12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN2CCC[C@H]2CN1
Temperature: 60 °C

Procedure:
1,1-Dimethylethyl (2S)-2-{[(chloroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (D11; 1.24, 4.5 mmol), was dissolved in 20 ml of DCM and treated with TFA (5 ml) at room temperature. After 1 h complete conversion into the desired material was observed and the reaction mixture was loaded onto a SCX cartridge. The product obtained after elution with 2M NH3 in MeOH was then dissolved in acetonitrile (30 ml) and treated with sodium carbonate (1.43 g, 10.34 mmol). The reaction mixture was heated at 60° C. for 6 hours; the crude obtained after removal is purified by flash-chromatography eluting with dichloromethane/MeOH 95/5 affording 310 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:3]1[C:2]([Cl:1])=[C:14]([Cl:15])[C:6]2[S:7][C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(CC(C)C)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a mixture of 10 g of 6,7-dichloro-5-hydroxy-2-isobutylbenzo[b]thiophene and 200 ml of 2-butanone is added a mixture of 6.9 g of ethyl bromoacetate in 50 ml of 2-butanone and by 6.6 g of potassium carbonate and 3.4 ml sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 2 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and 100 ml of ether. The organic layers are combined, washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give a solid. Recrystallization from ethyl ether and hexane gives 12 g of ethyl[(6,7-dichloro-2-isobutylbenzo[b]-thien-5-yl)oxy]acetate, mp 75°-76°.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]=[CH2:14])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:14][O:23]1)[CH3:2]
Reactant: C=Cc1ccc2c(c1CC)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1c(C2CO2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-ethyl-5-vinyl-2-benzofuran-1(3H)-one (1.1 g, 5.85 mmol) in 50 mL of DCM was slowly added mCPBA (3.60 g, 85% purity, 17.6 mmol) in 50 mL of DCM at 0° C. Warmed to room temperature, the mixture was stirred for 3 days. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers were combined, washed with brine and concentrated. The residue was purified by column chromatography to give product 4-ethyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
64 mg (0.23 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 64 mg (0.23 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred for 1 h at RT. Then 40 mg (0.15 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added and the mixture was stirred overnight. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10]O.[ClH:12]>>[ClH:12].[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CNCCCCC(=O)O
Reactant: CO
Agent: Cl
Product: CNCCCCC(=O)OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A stirred solution of 1-methyl-2-piperidinone (4.40 mL, 40.0 mmol) in aqueous sodium hydroxide (4 M, 11.0 mL, 44.0 mmol) was heated at 100° C. for 15 h. The reaction mixture was cooled to room temperature and then acidified to pH 2 with concentrated hydrochloric acid. The mixture was then concentrated under reduced pressure to give crude 5-methylaminopentanoic acid as a pinkish white solid. To the crude 5-methylaminopentanoic acid was added MeOH (40.0 mL, 987 mmol) and concentrated hydrochloric acid (0.33 mL, 4.0 mmol). The resulting cloudy solution was heated at 60° C. for 39 h at which time LC-MS showed remaining starting material. Additional concentrated hydrochloric acid (0.33 mL, 4.0 mmol) was added and the resulting mixture was heated at 60° C. for 33 h and then at 65° C. for an additional 24 h. LC-MS showed remaining starting material. The reaction mixture was concentrated under reduced pressure and a solution of hydrogen chloride in MeOH (1.25 M) was added to the residue. The resulting mixture was heated at 60° C. for 72 h at which time no remaining starting material was observed by LC-MS. The reaction mixture was partially concentrated under reduced pressure and the solid material that formed was removed by filtration, washing with MeOH. The filtrate was then concentrated under reduced pressure to provide methyl 5-methylaminopentanoate hydrochloride (7.57 g, 100% yield) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([C:35]3[CH:34]=[N:33][C:32]([NH2:31])=[N:37][CH:36]=3)[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
2-Chloro-7-methyl-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine (105 mg) was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 273. NMR (CDCl3): 1.37 (6H, d, J=6.8), 2.44 (3H, s), 2.63-2.66 (4H, m), 3.18-3.25 (1H, m), 3.43-3.46 (4H, m), 3.86 (2H, s), 3.89-3.91 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 9.35 (2H, s). MS (ESI+): MH+ 533.31 (40%)