Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.Cl>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([O:10][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1C(O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C1C(O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
A solution containing 3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (14.8 g, 60 mmol) in DCM (150 mL) was cooled to 0° C. To this solution was added imidazole (5.4 g, 79 mmol) followed by t-butyl-dimethylsilyl-chloride (10 g, 66 mmol) in two portions. The reaction mixture was warmed to ambient temperature over 1 h. After 5 h, the solution was diluted with 1M HCl and extracted twice with DCM. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 21.2 g (99%) of 3-(tert-Butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ4.38-4.34 (m, 1H), 4.18 (br s, rotomers, 0.5H), 4.04 (app d, J=2.1 Hz, rotomers, 0.5H), 3.74 (s, 3H), 3.62-3.50 (m, 2H), 2.04-1.96 (m, 1H), 1.85-1.78 (m, 1H), 1.46 (s, minor rotomer), 1.41 (s, 9H), 0.92 (s, minor rotomer), 0.86 (s, 9H), 0.11 (s, 6H), 0.09 (s, minor rotomer) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH2:16])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH:16][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1cccn2nc(C3(CN)CC3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccn2nc(C3(CNC(=O)C(C)C)CC3)nc12
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere C-[1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl]-methylamine (0.05 g, 0.23 mmol) was dissolved in THF (1 mL) and Et3N (0.048 mL, 0.35 mmol). Isobutyryl chloride (0.03 mL, 0.29 mmol) was added. Stirring for 30 min. Aq. NaHCO3 and H2O was added. The aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford N-[1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-isobutyramide as a solid.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH:20]([C:18]1[N:19]=[C:15]([CH2:14][CH2:13][C:11]2[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=[C:2]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:3]=[C:4]3[CH:12]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(O)nc3c2)n1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Reaction time: 24 h

Procedure:
The 2-hydroxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4 H-pyrido[1,2-a]-pyrimidin-4-one (500 mg) obtained in (A) was dissolved in methylene chloride (20 ml), added with triethylamine (0.26 ml) and p-toluenesulfonyl chloride (360 mg) and stirred for 24 hours under nitrogen atmosphere. The reaction solution was added with morpholine (0.83 ml) and stirred for 12 hours, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (273 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])=[O:14])[N:3]=2)=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: C[C@H](NC(=O)c1nc(Br)c2ccccc2c1O)C(=O)O
Product: C[C@H](NC(=O)c1nc(Sc2ccc(Cl)cc2)c2ccccc2c1O)C(=O)O
Temperature: 210 °C
Yield: 6.1 %

Procedure:
To a solution of 250 mg of (S)-2-{[1-bromo-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid in 0.7 ml of 1-methyl-2-pryrrolidinone was added 433 mg of 4-chloro-benzenethiol. The solution was heated at 210° C. for 30 min. using a CEM Discover microwave reactor. The solution was concentrated under vacuum. The resultant residue was crystallized from methanol to yield 18 mg of a tan solid; MS (−): m/z 401.10 (M−1)
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.C(O)C>[NH2:2][CH2:1][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1
Reactant: N#CCN1CCN(CCO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: NCCN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 4-(cyanomethyl)piperazine-1-ethanol (1.69 g, 10 mmol) in THF (20 ml) was added to a solution of lithium aluminum hydride in THF (20 ml, 20 mmol) in an argon stream with ice cooling, the mixture was stirred at room temperature for 5 minutes and heated to reflux for 90 minutes. The reaction solution was allowed to cool, diluted with ethanol with ice cooling and stirred at room temperature for 15 minutes after adding an aqueous 1N sodium hydroxide solution thereto. This was filtered off through celite and the filtrate was concentrated in vacuo to provide 4-(aminoethyl)piperazine-1-ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.Br[C:15]1[CH:16]=[C:17]([S:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:23])=[O:22])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>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.CN(C=O)C.O1CCOCC1>[CH2:27]([N:24]([CH2:25][CH3:26])[S:21]([C:17]1[CH:18]=[N:19][CH:20]=[C:15]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:16]=1)(=[O:22])=[O:23])[CH3:28]
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: CCN(CC)S(=O)(=O)c1cncc(Br)c1
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: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)S(=O)(=O)c1cncc(-c2cc3ccccc3n2C)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A flask is charged with 1-methyl-1H-indol-2-ylboronic acid (90 mg, 0.512 mmol), 5-bromo-N,N-diethylpyridine-3-sulfonamide (100 mg, 0.341 mmol) and polymer supported Pd(PPh3)4 (189 mg, 0.017 mmol), and the flask is flushed with N2 for 5 min. 1,4-Dioxane (10 mL) and 2M K2CO3 in water (0.512 mL, 1.023 mmol) are added under N2 and the mixture is stirred at 90° C. under N2 for 2 h. The mixture is then cooled to room temperature and DMF (4 mL) is added. The mixture is concentrated in vacuo and the residue is filtered and the filtrate is purified by Xterra RP18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give N,N-diethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.1 Hz, 6H), 3.29 (d, J=7.1 Hz, 4H), 3.80 (s, 3H), 6.85 (s, 1H), 7.08-7.14 (m, 1H), 7.26 (td, J=7.71, 1.26 Hz, 1H), 7.56 (dd, J=8.3, 0.5 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.33 (t, J=2.1 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H), 9.10 (d, J=2.2 Hz, 1H). HRMS: (ESI) m/z 344.1428 [(M+H)+ Calcd for C18H22N3O2S 344.1427].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4=[CH:24][S:25][CH:26]=[C:20]4[NH:19][C:18]3=[O:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4=[CH:24][S:25][CH:26]=[C:20]4[N:19]([C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])[C:18]3=[O:27])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2cscc2c(=O)n1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)n1c(=O)n(CCN2CCC(=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
A mixture of 3-[2-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione of Example 4 (0.80 g, 1.7 mmol), trimethylacetyl chloride (0.25 ml, 2.0 mmol) and triethylamine (0.84 ml, 6.0 mmol) in methylene chloride (20 ml) was stirred at room temperature for 16 hours. The reaction mixture was washed with water (2×30 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel 60 (80 g) using 1% methanol in methylene chloride as the eluant, to give the title compound (0.35 g, 37% yield) as a colorless solid, mp 69°-72° C. IR(KBr): 1595, 1660 and 1715 cm-1 ; MS (DCI), m/z 564 (MH+); 1H NMR (CDCl3): δ 1.44 (s, 9H), 2.34 (t, J=5 Hz, 4H), 2.61 (t, J=5 Hz, 4H), 2.67 (t, J=7 Hz, 2H), 4.17 (t, J=7 Hz, 2H), 6.58 (d, J=3 Hz, 1H), 6.96-7.08 (m, 8H) and 8.25 (d, J=3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[Li]CCCC.[C:18](=[O:20])=[O:19].[OH-].[Na+]>C1COCC1.C(OCC)C>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]([OH:20])=[O:19])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=C=O
Reactant: Clc1nccc2ccc(Br)cc12
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccnc(Cl)c2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a suspension of 7-bromo-1-chloroisoquinoline (2.000 g, 8.247 mmoles) in THF (12 mL) and diethyl ether (12 mL) cooled down to −78° C. was added n-BuLi (3.96 mL, 9.9 mmol, 2.5M in hexanes). Stirred for five minutes and then bubbled carbon dioxide while venting with a needle for approximately one minute. The reaction mixture was warmed up to 0° C. and 15 mL of a 1N aqueous sodium hydroxide were added. The mixture was diluted with diethyl ether stirred for 18 h. The organic and aqueous layers were separated and the organics were washed with 1N aqueous sodium hydroxide and water. The aqueous fractions were combined and acidified to pH 4 with 1N aqueous hydrochloric acid. The resulting solids were collected by filtration and dried to give the title compound (1.252 g, 73%). +ESI (M+H) 208.1 1H NMR (400 MHz, DMSO-d6) d ppm 13.58 (br. s., 1H) 8.86 (m, 1H) 8.43 (d, J=5.67 Hz, 1H) 8.33 (dd, J=8.61, 1.57 Hz, 1H) 8.19 (d, J=8.41 Hz, 1H) 8.01 (dd, 1H)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1.[NH:29]1[CH:33]=[N:32][CH:31]=[N:30]1>>[CH:23]1([O:22][C:19]2[CH:18]=[CH:17][C:16]([N:13]3[CH:14]=[CH:15][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:32]5[CH:31]=[N:30][N:29]=[CH:33]5)=[CH:10][CH:9]=4)[C:12]3=[O:28])=[CH:21][CH:20]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: c1nc[nH]n1
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(OC2CCCC2)cc1
Product: O=c1n(-c2ccc(OCCn3cnnc3)cc2)ccn1-c1ccc(OC2CCCC2)cc1

Procedure:
1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 1,2,4-triazole as described in example 5. The product with the molecular weight of 431.50 (C24H25N5O3); MS (ESI): 432 ([M+H]+) was obtained in this way.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](OC)=[O:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[CH2:24][CH2:23]2)[CH:9]=1.O>O1CCCC1>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[CH2:24][CH2:23]2)[CH:9]=1
Reactant: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a slurry of lithium aluminum hydride (46 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added a solution of methyl 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (400 mg, 0.96 mmol) in tetrahydrofuran (10 mL) at 0° C. under a nitrogen atmosphere. After being allowed to warm to room temperature and stirred for 2 hours, the reaction mixture was cooled to 0° C. and treated with water (0.2 mL) to quench the reaction. The resulting mixture was stirred for 30 minutes, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 321 mg of the desired product as a white solid (yield was 86%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH2:15][CH3:16]>ClCCl>[CH2:14]([NH:17][C:18]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:19])[CH2:15][CH3:16]
Reactant: CCCN=C=O
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: ClCCl
Product: CCCNC(=O)n1cc(F)c(N=CN(C)C)nc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 7 milliliter (mL) screw-cap vial were added dichloromethane (CH2Cl2; 5 milliliters (mL)), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (200 milligrams (mg), 1.09 millimoles (mmol)), and propyl isocyanate (94 mg, 1.10 mmol). The mixture was shaken at room temperature for 16 hours (h). After evaporation and recrystallization of the crude product from CH2Cl2 and heptane, the title compound was isolated as a white solid (274 mg, 94%): mp 266-268° C.; 1H NMR (300 MHz, CDCl3) δ10.42 (br s, 1H), 8.84 (s, 1H), 8.46 (d, J=6.6 Hz, 1H), 3.39-3.30 (m, 2H), 3.25 (s, 6H), 1.70-1.57 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); ESIMS m/z 270 ([M+H]+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:17]([CH:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:25])[N:15]=[C:14]2[S:26][C:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[C:13]=12)[CH:2]=[CH2:3].C(O[C:37]([CH3:40])([CH3:39])[CH3:38])(=O)C.S(=O)(=O)(O)O>ClCCl>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:17]([CH:18]([O:24][C:37]([CH3:40])([CH3:39])[CH3:38])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:25])[N:15]=[C:14]2[S:26][C:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[C:13]=12)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)ccc1-c1c(C(O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Reactant: CC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C=CCOc1cc(C)ccc1-c1c(C(OC(C)(C)C)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a stirred solution of ethyl {4-[2-(allyloxy)-4-methylphenyl]-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl}(hydroxy)acetate (Step 7, 720 mg, 1.59 mmol) in dichloromethane (2.5 mL) was added tert-butyl acetate (2.5 mL) followed by concentrated sulphuric acid (244 μL, 4.78 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched by addition of a 1 M aqueous sodium hydroxide solution until the solution was at pH 5. The volatile solvents were removed in vacuo, and the remaining aqueous layer was extracted with ethyl acetate (30 mL). The organic layer was washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 40%). Product containing fractions were concentrated in vacuo to give a mixture of diastereoisomers of the title compound as a colourless oil, 370 mg, in a 45% yield. Material is shown to be a mixture of diastereomers, in an approximately 80:20 ratio.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH3:2].[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:15]([CH3:29])[O:14][N:13]=1>>[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:10][C:4]3[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[C:6]([CH3:9])[N:5]=3)(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[C:15]([CH3:29])[O:14][N:13]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc(C)nc1N
Product: CCc1ccc(C)nc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Yield: 58.2 %

Procedure:
The title compound (70.1 mg) was prepared from 3-ethyl-6-methylpyridin-2-amine (0.091 g, 0.3 mmol) and 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (0.136 g, 0.45 mmol), following the procedure described for Intermediate 54. LCMS (2 min, formic) Rt 1.02 min, m/z (ES+) 402 (M+H).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Cl.[K].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>CN(C)C=O>[Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18]
Reactant: ClC/C=C/CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a solution of 10 g of 1,4-dichloro(trans) 2-butene in 100 ml of N,N-dimethylformamide was added 16.5 g of phthalimide potassium with ice cooling. The mixture was stirred at room temperature for 8 hours, the mixture was subjected to extraction with water-ethyl acetate, and the organic layer was distilled to remove the solvent. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), giving 9.6 g of N-[4-chloro(trans) 2-butenyl]phthalimide (yield 51% ).
Reaction SMILES: [NH:1]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:2]([C:19]([NH:21][C@@H:22]([C:35]([NH:37][C@H:38]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH:33]=[O:34])[CH:25]=1)=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=1.[Cl-].[NH+]1C=CC=CC=1>CN(C=O)C>[NH:1]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:2]([C:19]([NH:21][C@@H:22]([C:35]([NH:37][C@H:38]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH:33]=[O:34])[CH:25]=1)=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc3cn(C=O)c4ccccc34)C(=O)N[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.83 h
Yield: 73.5 %

Procedure:
To a solution of Boc-His(Tos)-D-Trp(CHO)-Phe-OBzl (1.16 g) in DMF (35 ml) was added pyridinium chloride (1.6 g) at room temperature. After stirring for one and half an hour, additional pyridinium chloride (0.4 g) was added and the mixture was stirred for additional 50 minutes. After evaporation, the residue was solidified with water, filtered, washed with 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water, and dried. The powder was subjected to column chromatography on silica gel (100 g) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were combined and evaporated. The residue was dissolved in ethanol and reprecipitated with water, filtered and dried to give Boc-His-D-Trp(CHO)-Phe-OBzl (0.70 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:34])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[OH:21])=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:33]=1.C[O-].[Na+].C([NH2:40])=O>>[Br:1][C:2]1[C:3]([F:34])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:21])[CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]4)=[C:14]([C:16](=[O:18])[NH2:40])[N:15]=[C:7]3[C:6]=2[CH:33]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1C(O)C1CN(C(=O)OC(C)(C)C)C1)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC(C(O)c2c(C(N)=O)nc3n2C2CC(C2)c2cc(F)c(Br)cc2-3)C1
Yield: 82 %

Procedure:
tert-butyl 3-((10-bromo-2-carbamoyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepin-3-yl)(hydroxy)methyl)azetidine-1-carboxylate was prepared similarly to as described in General Procedure L. Methyl 10-bromo-3-((1-(tert-butoxycarbonyl)azetidin-3-yl)(hydroxy)methyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 160 mg (82% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:23](OC)=[O:24])[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:12][CH:13]=1)([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:4][C:2]([Si:5]([CH3:27])([CH3:28])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH2:23][OH:24])[CH:9]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)ccc1-c1cc(OC)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2CO)c1
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
A 100 mL round bottom flask was charged with 83.18A (0.82 g, 2.0 mmol) and THF (10 mL). To the solution was added LAH (1.0 M in THF) (available from Aldrich) (2.0 mL, 2.0 mmol) dropwise at room temperature. The mixture was stirred for 10 minutes, quenched with aqueous Rochelle salt, and diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-25% EtOAc/hexane) to afford 83.18B (0.73 g, 96% yield) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:4][CH2:3]1.[NH2:15][C:16]1[C:25]([C:26](O)=[O:27])=[C:19]2[N:20]=[CH:21][C:22]([F:24])=[CH:23][N:18]2[N:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN1C(=O)CCC1.CCOC(C)=O>[NH2:15][C:16]1[C:25]([C:26]([NH:14][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:27])=[C:19]2[N:20]=[CH:21][C:22]([F:24])=[CH:23][N:18]2[N:17]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)O
Reactant: CN1CCN(c2ccncc2N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)pyridin-3-amine (prepared according to methods similar to the one depicted in Preparation N-1, described below) (588.1 mg, 3.059 mmol), 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a (prepared according to methods similar to the ones depicted in the sequence Step 1-Step 2 of Preparation 2a) (500 mg, 2.549 mmol), TBTU (1.146 g, 3.569 mmol) and Et3N (515.9 mg, 710.6 μL, 5.098 mmol) in NMP (7 mL) was stirred at 110° C. in a sealed tube, for 20 h. The reaction mixture was diluted with EtOAc, washed with a saturated bicarbonate aqueous solution and brine. The organic was dried over MgSO4 and concentrated after filtration. The solid was triturated in DCM and then filtered off. It was further purified by Fractionlynx HPLC to yield the title compound as a colourless solid. MS (ES+) 371.3.