Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:23]=[C:22]4[C:17]([CH:18]=[C:19]([N+:24]([O-])=O)[CH:20]=[CH:21]4)=[N:16]3)[N:10]=2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:23]=[C:22]4[C:17]([CH:18]=[C:19]([NH:24][C:27](=[O:29])[CH3:28])[CH:20]=[CH:21]4)=[N:16]3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2cn(-c3nccc(Nc4ccc(Cl)cc4)n3)nc2c1
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2cn(-c3nccc(Nc4ccc(Cl)cc4)n3)nc2c1
Temperature: 100 °C
Yield: 6 %

Procedure:
(4-Chloro-phenyl)-[2-(6-nitro-indazol-2-yl)-pyrimidin-4-yl]-amine (500 mg, 1.36 mmol) and iron powder (152 mg, 2.73 mmol) was suspended in acetic anhydride (10 mL) and acetic acid (10 mL). The reaction mixture was heated to 100° C. over night and concentrated in vacuo. Water (30 mL) was added followed by extraction with chloroform (3×30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate, filtrated and concentrated in vacuo to give the crude product as a brown solid. Preparative HPLC gave N-{2-[4-(4-chloro-phenylamino)-pyrimidin-2-yl]-2H-indazol-6-yl}-acetamide (35.2 mg, 6%) as a purple solid. LC-ESI-HRMS of [M+H]+ shows 379.1073 Da. Calc. 379.107412 Da, dev. −0.3 ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])[C:10](=[O:23])[NH:9][CH2:8]2)=[O:4].[OH-].[Na+]>>[F:22][C:16]1[CH:17]=[C:18]([I:21])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]1[CH:12]=[C:11]2[C:7]([CH2:8][NH:9][C:10]2=[O:23])=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2c(cc1Nc1ccc(I)cc1F)C(=O)NC2
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCc2cc(C(=O)O)c(Nc3ccc(I)cc3F)cc21
Temperature: 60 °C
Yield: 116.6 %

Procedure:
To a suspension of 6-(2-fluoro-4-iodo-phenylamino)-1-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (220 mg, 0.52 mmol) in IMS (7 mL) was added aqueous sodium hydroxide solution (1.3 mL, 1M, 1.30 mmol). The reaction mixture was heated at 60° C. for 3 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo to remove the IMS and the resultant solution was acidified to pH ˜5 by addition of aqueous hydrochloric acid (1M) causing a precipitate to form. The product was collected by filtration and dried under vacuum at 45° C. to yield the title compound as a brown solid (250 mg, >100%). LCMS (Method B): RT=3.07 min, M+MeCN+H+=454.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([O:37]CC)=[O:36])=[C:21]([C:23]3[CH:28]=[N:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:25][N:24]=3)[N:22]=2)[CH2:14][C@@H:13]1[O:40][CH2:41][CH3:42])=[O:10].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([OH:37])=[O:36])=[C:21]([C:23]3[CH:28]=[N:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:25][N:24]=3)[N:22]=2)[CH2:14][C@@H:13]1[O:40][CH2:41][CH3:42])=[O:10]
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OCC)C2)nc1-c1cnc(N2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCO[C@H]1CN(c2nc(-c3cnc(N4CCCCC4)cn3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To the solution of ethyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate (Example 67, 120 mg, 0.188 mmol) in methanol (20 mL) was added 2N sodium hydroxide (3 mL) in a dropwise fashion at 0° C. The reaction mixture was stirred overnight and then concentrated under reduced pressure to dryness. The resulting residue was diluted with water (20 mL) and extracted with ethyl acetate to remove any organic impurities. The aqueous layer was passed through celite bed and acidified with 2N hydrochloric acid. The precipitated product was collected by filtration and dried to afford 35 mg (31.8%) of 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxy piperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylic acid as a yellow solid.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:11])[CH2:6][CH2:7][CH2:8][C:9]#[CH:10].[N:13]#[C:14][NH2:15]>>[ClH:1].[CH2:6]([C:5]1[N:11]=[C:14]([NH2:15])[NH:13][CH:4]=1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCCCc1c[nH]c(N)n1
Yield: 90 %

Procedure:
2-Amino-hept-6-ynoic acid methyl ester hydrochloride (2.00 g, 10.4 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (1.75 g, 90%) as a pale oil (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CDCl3) δ 6.68 (bs, 2H), δ 6.24 (s, 1H), δ 2.51 (t, 2H), δ 2.17 (t, 1H), δ 1.95 (s, 1H), δ 1.74 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 148.3, 132.7, 111.6, 84.4, 69.1, 28.0, 26.0, 18.2 ppm; HRMS (ESI) calcd for C10H16N3 (M+) 150.1026. found 150.1029.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]([S:24]([CH3:27])(=[O:26])=[O:25])C(=O)OC(C)(C)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CCCCCC.C(OCC)(=O)C.CCCCCC>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:24]([CH3:27])(=[O:26])=[O:25])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)S(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
In dichloromethane (4 ml) was dissolved t-butyl N-[5-[(4-chlorophenyl)sulfonyl]-5(2,5-difluorophenyl)pentyl]-N-methylsulfonylcarbamate (108 mg, 0.196 mmol), followed by the addition of trifluoroacetic acid (1 ml) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane, washed successively with water, a saturated aqueous solution of sodium bicarbonate, and brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated, whereby the solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (75.5 mg, 0.167 mmol, 85%) was obtained as a white powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30]C)=O)(C)(C)C.[OH-].[Na+]>C(O)C>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:18]3[C:19](=[O:30])[NH:20][N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:23]=3)[NH:8]2)=[CH:12][CH:13]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(Br)cc2n1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1cc2ccc(Br)cc2[nH]1
Temperature: 150 °C
Yield: 65.5 %

Procedure:
40 mg 6-Bromo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester are dissolved in 0.5 mL ethanol. 0.58 mL 1 N aqueous sodium hydroxide are added. The reaction mixture is heated to 150° C. in a microwave oven for 15 minutes. Purification by HPLC affords 20 mg (50%) 4-(6-bromo-1H-indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:16](=[O:17])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-5-chloropyridine (1.05 g, 8.2 mmol) was suspended in 15 mL dry DCM under Ar, added dry pyridine (0.66 mL, 8.2 mmol), cooled to 0° C. and added 4-nitrophenol chloroformate. A white precipitate forms rapidly. Stirred at ambient temperature for 1 hour, filtered off solid, washed with water and then DCM. A white solid recovered which is consistent with title compound. (2.1 g, 88%) 1H-NMR (D6-DMSO)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)=[N:30][OH:31])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc2ncccc2c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1ccc2ncccc2c1)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-quinolin-6-yl-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (5.6:1) as a white foam, MS (ESI+): m/z=445.0907 ([M+H]+, 1Br).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>CCO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([O:11][C:10]([F:9])([F:19])[F:20])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)ncn2)cc1
Yield: 84 %

Procedure:
4,6-Dichloropyrimidine (250 mg, 3.3 mmol) and 4-trifluoromethoxy aniline (330.5 mg, 1.8 mmol) were dissolved in EtOH and DIEA (312.5 uL, 1.8 mmol) was added and the mixture was refluxed for 4 h. It was then cooled, concentrated and work-up with ethyl acetate. The organic layer was separated and dried (Na2SO4). Concentrated and purified by silica-gel column chromatography (Ethyl acetate/hexane). 400 mg (84% Yield). MS m/z 290.04 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][O:28][NH2:29])([CH3:22])([CH3:21])[CH3:20].Cl>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:29][O:28][CH2:27][CH2:26][NH:25][C:24](=[O:30])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2cc3ccncc3[nH]2)cc1
Reactant: CC(C)(C)OC(=O)NCCON
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=NOCCNC(=O)OC(C)(C)C)c2cc3ccncc3[nH]2)cc1

Procedure:
(4-Methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 100) (130 mg, 0.55 mmol) and tert-butyl[2-(aminooxy)ethyl]carbamate (99 mg, 0.56 mmol) were combined in ethanol (8 mL). The pH of the mixture was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 14 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by column chromatography (silica gel, 75 to 100% ethyl acetate in hexanes) produced tert-butyl 2-[[[(4-methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (geometry of the oxime double bond undefined).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17](C)=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1.Cl[C:26]1C=C(C=CC=1)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([CH3:26])[N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2nc([S@@](=O)Cc3nc(C)cc(OC)c3C)[nH]c2c1
Temperature: 0 °C

Procedure:
(5)6-methoxy-2[[(4methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]1H-benzimidazole (16.2 g; 0.0492 mol)) is reacted with m-chlorobenzoic acid (13.6 g; 0.0537 mol) with CH2Cl2 acting as a solvent at a pH of 8.6. The pH is maintained by the presence of KHCO3 (5.6 g; 0.056 mol) acting as a buffer. The temperature is maintained at about 0° C. during the addition. Diluted NaOH is added to a pH above 12 and the CH2Cl2 phase is separated off. Dimethylformamide (4.7 g) is charged to the water phase and the pH is kept above 9, whereupon crystals a mixture of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole are formed. The crystals are filtered off and are washed with water and methanol at a temperature of about 0° C. The washed crystals are then dried under vacuum and are found to predominantly contain 6-methoxy-2-[[(4-methoxy-3,5dimethyl-2-pyridinyl)methyl]sulfinyl]1H-benzimidazole.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][C:10]([C:13]#[N:14])=[CH:11][N:12]=2)=[CH:6][N:7]=1.[F:15][CH:16]([F:28])[O:17][C:18]1[C:19]([C:24]([NH2:27])([CH3:26])[CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1>CC#N>[F:28][CH:16]([F:15])[O:17][C:18]1[C:19]([C:24]([NH:27][C:2]2[N:3]=[N:4][C:5]([C:8]3[S:9][C:10]([C:13]#[N:14])=[CH:11][N:12]=3)=[CH:6][N:7]=2)([CH3:25])[CH3:26])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(N)c1ncccc1OC(F)F
Reactant: N#Cc1cnc(-c2cnc(Br)nn2)s1
Solvent: CC#N
Product: CC(C)(Nc1ncc(-c2ncc(C#N)s2)nn1)c1ncccc1OC(F)F
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a scintillation vial was added 2-(3-bromo-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (directly from above reaction), 2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-amine (100 mg, 500 μmol), and CH3CN (2 mL). The reaction was heated to 90° C. and stirred for 12 h. The reaction was then concentrated and purified using silica gel chromatography to afford 15 mg of 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:5][CH:4]=1)#[CH:2]
Reactant: CS(=O)(=O)Cl
Reactant: C#Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: C#Cc1ccc(NS(C)(=O)=O)cc1
Yield: 89.2 %

Procedure:
step 1—To a solution of 4-ethynyl aniline (4.00 g, 34.00 mmol) DCM (60 mL) at 0° C. was added sequentially pyridine (3.32 mL, 40.8 mmol) and dropwise addition of methanesulfonyl chloride (3.17 mL, 40.80 mmol). The reaction was stirred and allowed to warm from 0° C. to RT over 3 h then poured into a saturated aqueous NaHCO3 (150 mL). The aqueous layer was separated and extracted with DCM (2×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 5.92 g (88%) of N-(4-ethynyl-phenyl)-methanesulfonamide (80) as a solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[K+].[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:28])[CH2:26]Cl)[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CO>[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:28])[CH2:26][S:1][CH2:2][CH2:3][OH:4])[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(CCl)NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: OCCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(CSCCO)NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
0.12 ml of 2-mercaptoethanol was added to a solution of 0.13 g of 85% potassium hydroxide and 0.50 g of N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]-2-chloroacetamide [prepared as described in step (a) above] in 10 ml methanol, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, the concentrate was mixed with water, and the resulting aqueous mixture was extracted with chloroform. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.43 g (yield 77%) of the title compound as an oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[Si:23]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (970 g) in N,N-dimethylformamide (1000 mL) was added imidazole (591 g) at 0° C. Upon dissolution of the imidazole, tert-butyldimethylsilyl chloride (652 g) was added at 0° C. The reaction was stirred for 16 hours at room temperature, cooled to 0° C., and quenched with water (2.25 L). The mixture was extracted with ethyl acetate (4×), and the combined organic layer was washed with brine (3×), dried over magnesium sulfate, filtered, and concentrated to give 1-tert-butyl 2-methyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate. The residue was used directly without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Br[C:18]1[N:22]([CH3:23])[C:21]([CH3:24])=[N:20][CH:19]=1.[F-].[Cs+]>COCCOC.CO.CCOC(C)=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>[CH3:23][N:22]1[C:18]([C:9]2[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=2)=[CH:19][N:20]=[C:21]1[CH3:24]
Reactant: Cc1ncc(Br)n1C
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CO
Product: Cc1ncc(-c2ccc(N)cc2)n1C
Temperature: 150 °C
Yield: 56.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.053 g, 0.046 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.1 g, 0.456 mmol), 5-bromo-1,2-dimethyl-1H-imidazole (0.088 g, 0.502 mmol) and cesium fluoride (0.208 g, 1.369 mmol) in DME/MeOH (2/1, 2.9 mL). The reaction mixture was heated for 10 minutes at 150° C. under microwave irradiation. The reaction was diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified using Biotage silica gel column chromatography eluting with 1 to 5% MeOH/aq. NH3 (10/1) in DCM followed by filtration through a SCX-2 column to afford the title product as a white solid (48 mg, 56%). 1H NMR (500 MHz, CDCl3): δ 2.42 (s, 3H), 3.46 (s, 3H), 3.81 (br s, 2H), 6.71-6.74 (m, 1H), 6.85 (s, 1H), 7.12-7.14 (m, 1H).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:21].C1CCCCC1.N>C(OCC)(=O)C.CO>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:30][CH2:29]1)[CH3:35]
Reactant: CCN(CC)CCOCCC1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCN(CC)CCOCCC1CCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 71 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[2-[2-(diethylamino)ethoxy]ethyl]piperidine in a yield of 71% of theory. Colourless crystals, m.p. 119°-120° C. (cyclohexane), Rf 0.43 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: ethyl acetate/methanol/conc. ammonia 100/30/3, v/v/v)
Reaction SMILES: OO.[C:3]([C:5]1[C:6]([O:11][CH:12]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]2)=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:4].C(=O)([O-])[O-:35].[K+].[K+].O>CS(C)=O>[C:3]([C:5]1[C:6]([O:11][CH:12]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]2)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:35])[NH2:4]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(Oc2ncccc2C#N)C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(Oc2ncccc2C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
33% Aqueous hydrogen peroxide (1 mL) was added to a solution of tert-butyl (6RS,7SR)-6-[(3-cyanopyridin-2-yl)oxy]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) and potassium carbonate (45 mg) in DMSO (3 mL), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and HPLC to give the title compound (57 mg).