Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11]Br)[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1.[OH:21][CH2:22][C:23]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][O:21][CH2:22][C:23]2([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(Br)cc(CBr)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A flask was charged with 5-bromo-7-(bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (0.61 g, 1.45 mmol), tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.444 g, 1.52 mmol), and dimethylformamide (5 mL). The reaction was cooled to 0° C. and treated with sodium hydride (0.073 g, 3.05 mmol) in several portions. After stirring for 15 min, the ice bath was removed and stirring continued for 15 min. The reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The reaction was poured into diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 720 mg (79%) as a gum. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.38 (m, 4H), 7.24 (m, 1H), 7.13 (d, J=1.5 Hz, 1H), 5.65 (s, 2H), 4.81 (s, 2H), 3.76 (bs, 2H), 3.58 (t, J=8.2 Hz, 2H), 3.53 (s, 2H), 3.06 (m, 2H), 2.22 (m, 2H), 1.95 (m, 2H), 1.44 (s, 9H), 0.91 (t, J=8.2 Hz, 2H), 0.00 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.1, 145.5, 142.9, 130.5, 128.6, 127.4, 126.6, 126.5, 123.3, 122.2, 121.3, 116.0, 81.9, 80.0, 79.4, 68.5, 67.6, 41.9, 40.3 (br), 32.0, 28.6, 17.9, −1.3. Mass spec.: 630.14 (MH)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH2:14][NH:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[CH:17]1[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([CH2:14][NH:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([OH:25])[CH:17]1[CH3:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1C(=O)c2ccccc2C1NCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1C(O)c2ccccc2C1NCCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
An ice-cold suspension of 1.5 grams (0.040 mole) of lithium aluminum hydride in 35 ml of dry tetrahydrofuran is treated dropwise over a period of about 30 minutes with a solution of 10.4 grams (0.039 mole) of 3-benzylmethylamino-2-methylindan-1-one in 80 ml of tetrahydrofuran. The mixture is stirred at 0° for 4 hours and then quenched by the addition of ethylacetate, 2N sodium hydroxide and water. The solids are filtered, and the filtrate is dried over magnesium sulfate, filtered and evaporated to yield 3-benzylmethylamino-2-methylindan-1-ol as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Brc1ccccc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), bromobenzene (0.314 g, 2 mmol), K3PO4 (0.424 g, 2 mmol), CuI (19 mg, 0.1 mmol) and L-Proline (23 mg, 0.2 mmol) in dry DMF (3 mL) was stirred at 150° C. for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (83 mg). 1H NMR (HCl salt, CD3OD) d (ppm): 7.60 (t, 2H), 7.5 (t, 1H), 7.4 (d, 2H), 7.35 (s, 1H), 7.1 (d, 1H), 7.05 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.85-3.8 (m, 1H), 3.6-3.59 (m, 1H), 3.2-3.19 (m, 1H), 3.18 (s, 3H), 3-2.95 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: ClCCO[CH:5]([O:13][CH2:14][CH2:15][Cl:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.C[Si]([C:21]#[N:22])(C)C.C(C(C#N)=C(C#N)C#N)#N>C(#N)C>[Cl:16][CH2:15][CH2:14][O:13][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)[C:21]#[N:22]
Reactant: C[Si](C)(C)C#N
Reactant: Fc1ccc(C(OCCCl)OCCCl)cc1
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC#N
Product: N#CC(OCCCl)c1ccc(F)cc1

Procedure:
A solution containing 1-[bis-(2-chloroethoxy)methyl]-4-fluorobenzene (5.43 g), trimethylsilyl cyanide (4.06 mL) and tetracyanoethylene (520 mg) in acetonitrile (100 mL) was heated under reflux for four hours. The reaction solution was returned to room temperature and the solvent was evaporated under reduced pressure. Ethyl acetate and brine were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex, elution solvent: heptane/ethyl acetate) to obtain the title compound (4.3 g). The property values of the compound are as follows.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([C:17]([F:21])([F:20])[CH2:18][CH3:19])[N:13]=[CH:12][C:11]=2[C:10]([CH3:23])([CH3:22])[CH2:9]1)=O)(C)(C)C.[ClH:24]>CO>[ClH:24].[F:20][C:17]([C:14]1[N:13]=[CH:12][C:11]2[C:10]([CH3:22])([CH3:23])[CH2:9][NH:8][C:16]=2[CH:15]=1)([F:21])[CH2:18][CH3:19]
Reactant: CCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCC(F)(F)c1cc2c(cn1)C(C)(C)CN2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 6-(1,1-difluoro-propyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.398 g, 1.2 mmol), hydrochloric acid (5 M, 12 mL) and methanol (12 mL) was stirred at 20° C. for 16 h then evaporated in vacuo. The residue was azeotroped with methanol (×3) and toluene (×2) to give the title compound (0.3 g) as a solid. MS: [M+H]+=227.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH:25]=[CH:26][N:14]2[C:13]1=[O:27].S(=O)(=O)(O)O.[CH:33]([OH:35])=[O:34].O>C(OCC)(=O)C.CCCCCC>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:33]([OH:35])=[O:34])[N:14]2[C:13]1=[O:27]
Reactant: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reactant: O=CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=C(O)[C@@H]1CCCC2c3ccccc3CC(N3C(=O)c4ccccc4C3=O)C(=O)N21
Reaction time: 18 h

Procedure:
Combine (S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine (32 mg, 0.09 mmol) and sulfuric acid (1.0 mL, 95-98%) in a pressure vessel. Add 96% formic acid (200 μL) and quickly seal the vessel. After 18 hours, add water (10 mL). Extract the reaction mixture with ethyl acetate. Extract the organic layer with saturated aqueous potassium carbonate solution (5×10 mL). Combine the aqueous layers and carefully acidify with aqueous 12M hydrochloric acid solution. Extract with chloroform (5×15 mL). Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2/1 ethyl acetate/hexane containing 0.5% acetic acid to give the title compound. Rf =0.14 (silica gel, 2/1 ethyl acetate/hexane containing 0.5% acetic acid).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26].[OH-].[Li+]>O1CCOCC1.O>[CH2:12]([CH:11]([NH:10][C:9]1[C:4]([C:3]([OH:27])=[O:2])=[C:5]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:6]=[C:7]([CH3:16])[CH:8]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)O
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester (16 mg, 0.043 mmol) and lithium hydroxide (30 mg) in dioxane (1 ml) and water (1 ml) was stirred at rt over night. The mixture was quenched with water and adjusted to pH 7.0 and extracted with chloroform. The organic layer was dried and concentrated to give the crude material. The crude material was purified through silica gel column chromatography using 10% ethyl acetate in chloroform as eluent to give 7 mg of the title compound as white solid. 1H NMR (CDCl3) δ 9.12 (d, 1H), 6.87 (s, 2H), 6.16 (s, 1H), 3.35 (m, 1H), 2.29 (s, 3H), 2.10 (s, 3H), 2.07 (s, 6H), 1.4–1.6 (m, 4H), 0.94 (t, 6H) ppm.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:14]N1C(=O)C2=CC=CC=C2C1=O>[Co+2].C(O)(=O)C>[OH:14][C:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][C:1]([C:11]([OH:13])=[O:12])([CH2:8]3)[CH2:2]1)[CH2:4]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Co+2]
Solvent: CC(=O)O
Product: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 75 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 5.07 mol of 1-adamantanecarboxylic acid, 507 mmol of N-hydroxyphthalimide, 5.07 mmol of cobalt (II) acetylacetonato and 12500 ml of acetic acid was stirred at 75° C. under an oxygen atmosphere (1 atm) for 8 hours. The reaction mixture was concentrated, and was subjected to column chromatography on a silica gel (eluent: chloroform/methanol (8/1)), and the obtained purified product was further recrystallized with ethanol/n-hexane to give 3-hydroxy-1-adamantanecarboxylic acid (yield: 38%) at a conversion rate from 1-adamantanecarboxylic acid of 99%.
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH3:17])[C:7]=1[C:8]#[N:9])(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+]>C(O)C>[NH2:9][C:8]1[C:7]2[C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][S:1](=[O:4])(=[O:3])[N:2]=1
Reactant: CCCOc1cccc(NS(N)(=O)=O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a suspension of 2-sulfamoylamino-6-propoxybenzonitrile (Example 111a) (4.73 g, 18.53 mmol) in ethanol (65 mL), was added aqueous NaOH (2N, 18.6 ml, 37.06 mmol). The resulting clear solution was refluxed for 3 hours under nitrogen. After cooling to room temperature, the resulting solution was filtered, the filtrate was cooled to 0° C. and neutralized with 10% acetic acid. The resulting precipitate was collected by filtration, suspended in 50 ml of ethanol/water (1:1) and warmed to 40° C. for 20 min. The solid was collected by filtration to provide 4-Amino-5-(propyloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (4 g, 85%) as a pale yellow powder. M.p.: 229-230° C. 1H NMR (400 MHz, DMSO-d6) δ 0.96 (t, J=7.3 Hz, 3H), 1.81 (sext, J=7.3 Hz, 2H), 4.10 (t, J=6.7 Hz, 2H), 6.60 (d, J=8.6 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 7.44 (t, J=8.6 Hz, 1H), 7.81 (br s, 1H), 8.35 (br s, 1H), 10.93 (br s, 1H). 13C NMR (400 MHz, DMSO-d6) δ 11.07, 22.18, 71.41, 100.93, 105.64, 110.21, 135.53, 145.16, 158.47, 161.10. MS 256 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:33]([O:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[NH4+].[Cl-]>ClCCl.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][N:11]([C:41]([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:42])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)CNCc1cccc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)CN(Cc1cccc(Cl)c1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of the amine from Step D (754 mg, 1.93 mmol) and triethylamine (0.403 mL, 2.89 mmol) in 5 mL of dichloromethane at 0° C. was added benzylchloroformate (0.303 mL, 2.12 mmol). After 2 hours, the solution was poured into EtOAc and sat NH4Cl solution, and the organic layer was washed with sat. NaHCO3 soln. and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was purified by silica gel chromatography (30-40% EtOAc/hexane) to obtain the titled compound (360 mg) as a white foam.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.Cl[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([S:48]([CH:47]=[CH2:46])(=[O:50])=[O:49])[CH2:33][CH2:34]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:11]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC(Nc2ncc3c(n2)-c2c(c(C(=O)Nc4c(CC)cccc4CC)nn2C)CC3)CC1
Temperature: -78 °C
Yield: 55.5 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (300 mg, 0.606 mmol) under nitrogen, in dry dichloromethane (15 mL), DIPEA (0.527 mL, 3.03 mmol) and 300 mg of molecular sieves were added, and the mixture was cooled at −78° C. 2-chloroethanesulfonyl chloride (0.063 mL, 0.606 mmol) was added. Temperature was allow to rise to room temperature then the solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel (eluant: ethyl acetate/dichloromethane: 2/8) to give 185 mg of the title compound (56% yield).
Reaction SMILES: Cl.[C:2]([CH:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[NH:7]1)([O:4][CH3:5])=[O:3].[C:13]([CH2:18][CH2:19][C:20](Cl)=[O:21])([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>CC(C)=O>[C:13]([CH2:18][CH2:19][C:20]([N:7]1[CH:6]([C:2]([O:4][CH3:5])=[O:3])[CH:11]2[CH2:12][CH:8]1[CH2:9][CH2:10]2)=[O:21])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COC(=O)C1NC2CCC1C2
Reactant: CCOC(=O)CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)CCC(=O)N1C2CCC(C2)C1C(=O)OC

Procedure:
Using the method of Example 1, 4.45 g (0.0232 m) of 3-carbomethoxy-2-azabicyclo[2.2.1]heptane hydrochloride and 3-carbethoxypropanoyl chloride were reacted using triethylamine and acetone to give 4.59 g of syrupy 2-(3-carbethoxypropanoyl)-3-carbomethoxy-2-azabicyclo[2.2.1]heptane.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:15][C:14]([NH:13][C:4]1[N:3]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=1)([CH3:17])[CH3:16]
Reactant: C1CNCCN1
Reactant: CC(C)(C)Nc1nc(Cl)cc(N2CCCC2)n1
Product: CC(C)(C)Nc1nc(N2CCCC2)cc(N2CCNCC2)n1
Yield: 78.1 %

Procedure:
4-Chloro-2-(1,1-dimethylethylamino)-6-pyrrolidinopyrimidine is reacted with piperazine as described in Example 17 to obtain the title compound in a yield of 78.1%, m.p.: 162°-165° C.
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36](O)=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][C:24]=3[N:25]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:39][C@H:9]2[O:8][C:7](=[O:40])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH:42]1([S:45]([NH:48][C:49]([C@@:51]2([NH3+:56])[CH2:53][C@H:52]2[CH:54]=[CH2:55])=[O:50])(=[O:47])=[O:46])[CH2:44][CH2:43]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([NH:56][C@:51]2([C:49]([NH:48][S:45]([CH:42]3[CH2:44][CH2:43]3)(=[O:47])=[O:46])=[O:50])[CH2:53][C@H:52]2[CH:54]=[CH2:55])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][C:24]=3[N:25]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:39][C@H:9]2[O:8][C:7](=[O:40])[NH:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc2nc3c(nc2c1)O[C@@H]1C[C@@H](C(=O)O)N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCC3
Reactant: C=C[C@@H]1C[C@]1([NH3+])C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1nc3ccc(OC)cc3nc1O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution (0.1 M) of (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylic acid in CH2Cl2 was treated with (1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride (1.3 eq), DIEA (3 eq), DMAP (1.5 eq) and TBTU (1.45 eq). The resulting mixture was stirred at 20° C. for 18 h and then diluted with EtOAc. The solution was washed with aqueous HCl (0.2 M), saturated aqueous NaHCO3 and brine. The organic phases were dried and concentrated to give a residue that was purified by flash-chromatography (eluent 2.5% MeOH/CH2Cl2) to give the title compound (89%) as a solid. 13C NMR (100 MHz, DMSO-d6) δ 172.32, 170.63, 169.04, 159.86, 156.95, 154.74, 148.10, 140.41, 133.55 (2 signals), 128.94, 118.21, 117.58, 105.89, 74.88, 59.75, 58.71, 55.68, 54.13, 54.01, 40.13, 34.49, 34.04, 33.76, 32.68, 30.71, 30.43, 28.55, 27.69, 27.28, 26.38, 21.98, 18.49, 10.67, 5.69, 5.46; MS (ES+) m/z 767 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH3:22][C:23]([CH3:29])([CH2:27][CH3:28])[C:24](Cl)=[O:25].N1C=CC=CC=1.C(Cl)Cl>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:24](=[O:25])[C:23]([CH3:29])([CH3:22])[CH2:27][CH3:28])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(C)(C)C(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21
Yield: 89.8 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) was suspended in 1,2-dichloroethane (20 ml), and 2,2-dimethylbutanoyl chloride (538 mg) and pyridine (0.33 ml) were added thereto to the suspension, and the mixture was refluxed for 2 hours. Methylene chloride was added to the reaction mixture, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, crystals so precipitate were washed with ether, to thereby obtain 1.20 g of the title compound (Yield 89.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH2:36][CH2:37][O:38][CH2:39][CH:40]=1)CCC>>[O:38]1[CH2:37][CH:36]=[C:35]([C:2]2[N:7]=[C:6]3[CH2:8][N:9]([C:11]([C:13]4[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[CH:15][C:14]=4[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:26])[F:27])=[O:12])[CH2:10][C:5]3=[CH:4][CH:3]=2)[CH2:40][CH2:39]1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(C3=CCOCC3)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C4) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. White solid. MS (m/e): 497.4 [M+H]+, 100%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:12](=[O:24])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:19])=[O:18])[C:12](=[O:24])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Reaction time: 0.75 h

Procedure:
The product from Example 18 is dissolved in trifluoroacetic acid (170 ml) and left at room temperature for 1 h 45 min. Subsequently, the mixture is codistilled five times with toluene and the product is dried in a desiccator over phosphorus pentoxide/potassium hydroxide for 24 h. Yield: 11.8 g (93%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[O:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH:34]5[CH2:35][CH2:36][O:31][CH2:32][CH2:33]5)[CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C2CCOCC2)C1)C3
Yield: 44.5 %

Procedure:
A mixture of Example 80 (150 mg; 0.35 mmol; 1 eq.), tetrahydropyran-4-one (52 mg; 0.52 mmol; 1.5 eq.) and sodium triacetoxyborohydride (74 mg; 0.35 mmol; 1 eq.) in DCE (4 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to EA/MeOH/TEA, 90/10/2) afforded the title compound (80 mg, 45%) as white foam. 1H NMR (DMSO-d6) δ 7.41-7.31 (m, 1H), 6.99 (dd, J=11.5, 2.2 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 5.03-4.94 (m, 1H), 4.85-4.77 (m, 2H), 4.75-4.44 (m, 2H), 3.74-3.59 (m, 2H), 3.22-3.06 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.79-2.64 (m, 3H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.35-2.15 (m, 2H), 2.14-2.00 (m, 1H), 1.82-1.68 (m, 1H), 1.63-1.50 (m, 2H), 1.31-1.03 (m, 2H). HPLC (max plot) 95.1%, Rt 2.83 min. UPLC/MS: (MS+) 514.5 ([M+H]+).