Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)CCC.O.CCOC(C)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nccs2)n1
Temperature: 75 °C

Procedure:
A mixture of commercially available methyl 6-bromopicolinate (300 mg; 1.38 mmol), 2-(tributylstannyl)thiazole (623 mg; 1.66 mmol), and PdCl2(PPh3)2 (97 mg; 0.13 mmol) in anh. THF (8 ml) was heated to 75° C., under nitrogen, for 18 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded methyl 6-(thiazol-2-yl)picolinate as a pale yellow solid. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 220.95 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32]Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][O:20][CH2:30][O:31][CH3:32])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCO)CC1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In dichloromethane (60 ml), 4-tert-butoxycarbonyl-1-[(3-hydroxy-1-propyl)sulfonyl]piperazine (3.00 g) was dissolved. To the resulting solution, diisopropylethylamine (2.72 ml) was added, followed by the addition of methoxymethyl chloride (1.11 ml) under ice cooling. After stirring at room temperature for 15 hours, the reaction mixture was diluted with dichloromethane, washed with water, 5% aqueous citric acid solution and saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (3.32 g, 97%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15](COCC[Si](C)(C)C)[C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:3]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[NH:15][C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:3]1
Reactant: CN1CCC[C@@H](COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCC[C@@H](COc2ccnc3[nH]c4cnc(C#N)cc4c23)C1
Temperature: 75 °C
Yield: 80.9 %

Procedure:
(R)-4-(1-methylpiperidin-3-ylmethoxy)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (45 mg, 0.1 mmol) was dissolved in 1,4-dioxane (0.2 mL) and then treated with 48% HBr(aq) (0.2 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a pale yellow solid (26 mg, 70% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.97 (d, J=0.7, 1H), 8.54 (d, J=5.7, 1H), 8.44 (s, 1H), 7.04 (d, J=5.8, 1H), 4.28 (d, J=6.4, 2H), 2.88 (m, 1H), 2.65 (m, 1H), 2.27 (m, 1H), 2.19 (s, 3H), 1.97 (m, 2H), 1.83 (m, 1H), 1.74-1.66 (m, 1H), 1.59 (m, 1H), 1.28-1.18 (m, 1H), NH signal not observed. LCMS (method D): RT=7.182 min, M+H+=322.1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[Br:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:15][CH2:16][C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Br:1])=[O:18]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccccc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CBr)Nc1ccccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of 2-bromoaniline (2.0 g, 11.63 mmol) in 25 mL of dichloromethane was added pyridine (1.13 mL, 13.95 mmol). The solution was cooled to 0° C. and bromoacetyl chloride (1.01 mL, 12.79 mmol) was added over a 5 min. period. The cooling bath was removed and the reaction mixture was stirred at RT for 90 min and partitioned between 1N HCl and dichloromethane. The dichloromethane layer was successively washed with saturated aqueous sodium carbonate, brine, dried over sodium sulfate and concentrated to yield 2.9 g of the title compound, which was used as such for the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Cl:13][CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].O.C(OCC)(=O)C>N1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][S:17]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)CCCCl)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.61 mmol) methyl 4-amino-3-methyl-benzoate dissolved in 3 ml of pyridine are combined with 82 μl (0.67 mmol) 3-chloropropanesulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction solution is combined with water and ethyl acetate and then the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]5)=[O:28])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.060 g (0.463 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0153 g (0.134 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0231 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-195) as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([C:12]2[CH:16]=[C:15]([C:17](=[O:21])[CH:18]=[CH:19][CH3:20])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)(=O)C>[C:6]1([C:12]2[CH:16]=[C:15]([C:17](=[O:21])[CH2:18][CH:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:20])[O:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: CC=CC(=O)c1cc(-c2ccccc2)no1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CC(=O)c1cc(-c2ccccc2)no1)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyrrolidine (5 ml) was added to 1.1 g (5.2-mmol) of 3-phenyl-5-(2-butenoyl)isoxazole prepared above in the procedure (1). The resulting mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, so that a product formed was extracted in an organic layer. The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated, whereby 3-phenyl-5-{3- (1-pyrrolidinyl)butyryl}isoxazole was obtained as colorless oil. Analytical results of the crystals obtained: Yield: 1.35 g (92%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl>C(O)(C)C.O1CCOCC1.C(Cl)Cl>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[C:7]3[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: CN1CCN(C)c2c(N)cccc2C1=O
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCN(C)c2c(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cccc2C1=O
Temperature: 130 °C
Yield: 22.1 %

Procedure:
9-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (50 mg, 0.24 mmol) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methane sulfonamide (90 mg, 0.27 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (67 μL) was added, and the resulting mixture was heated to 130° C. in the microwave for 30 min. The resulting solution was diluted with CH2Cl2 (50 ml) washed with saturated aqueous NaHCO3 (2×50 ml), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes followed by 0-20% MeOH in EtOAc) to obtain N-{(1R,2R)-2-[5-Chloro-2-(1,4-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}methanesulfonamide as a beige foam (27 mg, 22%). LCMS: m/z=510.20 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.48 (m, 2H), 7.96 (s, 1H), 7.27 (m, 2H), 5.60 (m, 2H), 3.95 (m, 1H), 3.34 (m, 5H), 3.20 (s, 3H), 2.86 (s, 3H), 2.78 (s, 3H), 2.24 (m, 2H0, 1.83 (m, 2H), 1.39 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[OH-].[Na+].[CH2:15](Br)[CH3:16]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:15]([O:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])[CH3:16]
Reactant: CCBr
Reactant: CC(CO)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 60 %

Procedure:
To a mixture of t-butyl (2-hydroxy-1-methylethyl)carbamate (2.89 g) and tetrabutylammonium hydrogen sulfate (560 mg, 0.1 equiv) in toluene (33 mL) and 50% aqueous sodium hydroxide solution (6.6 mL, 5 equiv) was added ethyl bromide (1.85 mL, 1.5 equiv) at room temperature. The mixture was stirred at room temperature for 4 days. The reaction mixture was partitioned between water and ethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to provide the crude product, which was purified by silica chromatography (9:1 to 75:25 hexanes:ethyl acetate (EtOAc)) to provide the title compound (2.00 g, 60% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C@:22]1([CH3:34])[C:28]([F:30])([F:29])[C:27]([CH3:32])([CH3:31])[O:26][CH2:25][C:24](=S)[NH:23]1.[NH3:35]>C(OO)(C)(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C@:22]1([CH3:34])[C:28]([F:30])([F:29])[C:27]([CH3:32])([CH3:31])[O:26][CH2:25][C:24]([NH2:35])=[N:23]1
Reactant: N
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Agent: CC(C)(C)OO
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Yield: 31 %

Procedure:
In a manner analogous to that described in Example 2c), the ammonolysis of (R)-5-[2,4-difluoro-5-(6-trifluoromethyl-benzooxazol-2-yl)-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (110 mg, 217 μmol) with ammonia (7M in methanol; 2.14 ml) and tert-butylhydroperoxide (70% in water; 260 μl) yielded the title compound (33 mg, 31% yield). MS (ISP): m/z=490.2 [M+H]+.
Reaction SMILES: [OH-].[Na+].O.Cl.[CH2:5]([N:12]1[CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.ClCCCl>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([CH:14]2[CH2:15][CH2:16][CH2:17][N:12]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:13]2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCCN(Cc3ccccc3)C2)CC1
Yield: 126.8 %

Procedure:
20 ml of a 10% sodium hydroxide solution are added to a suspension of 9.96 g of 1-benzyl-3-piperidone monohydrochloride hydrate in suspension in 200 ml of DCM. The medium is stirred, and the organic phase is separated by settling out and then washed with a saturated NaCl solution. After drying over MgSO4, the organic phase is concentrated. The gum obtained is taken up in 180 ml of DCE, 10.1 g of Boc-piperazine and then 15.9 g of NaBH(OAc)3 are added and the medium is stirred at AT for 12 h. The medium is concentrated and then taken up in EtOAc. The organic phase is washed twice with a saturated NaHCO3 solution, and then with a saturated NaCl solution. After drying over MgSO4, the organic phase is concentrated, to give 18.63 g of the expected product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][CH2:16][CH:17]([N:20]1[CH2:23][CH:22]([NH2:24])[CH2:21]1)[CH2:18][F:19].C(NC(C)C)(C)C>O1CCOCC1>[F:15][CH2:16][CH:17]([N:20]1[CH2:23][CH:22]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:21]1)[CH2:18][F:19]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CN(C(CF)CF)C1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: NS(=O)(=O)c1ccc(NC2CN(C(CF)CF)C2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-3-nitrobenzenesulfonamide (0.225 g) and 1-(1,3-difluoropropan-2-yl)azetidin-3-amine (0.193 g) in dioxane (5 mL) was added diisopropylamine (0.832 mL). The reaction was sonicated and then heated to 100° C. After stirring overnight, the reaction was concentrated and loaded onto silica gel (GraceResolv 12 g) and eluted with a gradient of 0.5% to 3.5% methanol/dichloromethane to give the title compound.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:31][C:32]1([CH3:39])[NH:36][C:35](=[O:37])[CH2:34][C:33]1=[O:38].[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[C:49](Br)[C:50]([CH3:53])=[CH:51][CH:52]=2)=[CH:43][CH:42]=1>O1CCOCC1.CO>[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:52]=[C:51]([CH:34]3[C:33](=[O:38])[C:32]([CH3:39])([CH3:31])[NH:36][C:35]3=[O:37])[C:50]([CH3:53])=[CH:49][CH:48]=2)=[CH:45][CH:46]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: CC1(C)NC(=O)CC1=O
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under argon, in a heat-dried apparatus, 7.4 mg of Pd(OAc), 22 mg of di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine and 0.78 g of K3PO4 in 4.8 ml of air-free dioxane are introduced as initial charge. 203 mg of 5,5-dimethylpyrrolidine-2,4-dione and 659 mg of 3-(4-chlorophenyl)-6-methylbromobenzene are added and the mixture is stirred for 16 hours under reflux. The mixture is 10 then left to cool to room temperature, diluted with ca. 6 ml of methanol and filtered, and the filter residue is after-washed with ca. 3 ml of MeOH. The combined filtrates are concentrated by evaporation on a rotary evaporator. The residue is taken up in ca. 6 ml of water and rendered weakly acidic using 1 N hydrochloric acid. The precipitated solid is filtered off with suction and washed with ca. 3 ml of water. It is then washed from the filter with acetone and the filtrate is concentrated by evaporation. This gives 0.597 g of solid. Reversed-phase separation with water/acetonitrile (gradient) gives 93 mg (14% of theory) with a purity of 98.6% according to HPLC/MS.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[O:16][CH2:15][C:11]1([CH2:14][O:13][CH2:12]1)[C:5]12[CH2:9][O:8][C:7]([NH2:10])=[N:6]1.[C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1)#[C:21][CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1(/C=C/C(=O)/C=C/C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:20]([C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[C:4]3[C:17](=[CH:18][CH:19]=2)[O:16][CH2:15][C:11]2([CH2:14][O:13][CH2:12]2)[C:5]23[CH2:9][O:8][C:7]([NH2:10])=[N:6]2)[CH:26]=[N:27][CH:28]=1)#[C:21][CH3:22]
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Reactant: CC#Cc1cncc(B(O)O)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC#Cc1cncc(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)CO3)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
The mixture of 6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (650 mg, 2.00 mmol), [5-(prop-1-yn-1-yl)pyridin-3-yl]boronic acid (644 mg, 4.00 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) (92 mg, 0.10 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (164 mg, 0.400 mmol), and K3PO4 (1.70 g, 8.00 mmol) in DMF (13 mL) was stirred for 16 hours at 110° C. under argon atmosphere. The precipitate formed was removed by filtration with celite and washed with CHCl3. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl3:MeOH=99:1-95:5) to give 6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (310 mg).
Reaction SMILES: N.C1(C[NH2:9])CCCCC1.[O:10]=[C:11]1[C:19]2([CH2:23][O:22][C:21]3[CH:24]=[C:25]4[C:29](=[CH:30][C:20]2=3)[CH2:28][CH2:27][O:26]4)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][CH:33]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>ClCCl>[O:10]=[C:11]1[C:19]2([CH2:23][O:22][C:21]3[CH:24]=[C:25]4[C:29](=[CH:30][C:20]2=3)[CH2:28][CH2:27][O:26]4)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:9])=[O:38])=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: NCC1CCCCC1
Agent: N
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: ClCCl
Product: NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using ammonia in dry dichloromethane to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.78 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.20-7.07 (m, 2H), 6.99 (t, J=7.4 Hz, 1H), 6.85 (s, 1H), 6.71 (d, J=7.6 Hz, 1H), 6.41 (br s, 1H), 6.35 (br s, 1H), 6.20 (s, 1H), 4.94 (ABq, 2H), 4.78 (ABq, 2H), 4.46 (t, J=8.5 Hz, 2H), 2.91 (t, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.6, 168.7, 161.5, 160.9, 141.4, 139.3, 132.7, 132.1, 128.4, 127.8, 127.0, 123.6, 123.3, 119.6, 118.4, 108.8, 92.8, 80.2, 72.0, 57.3, 43.4, 28.6; MS (ES+) m/z 413.1 (M+1).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8]C)=[O:6])=[N+:2]=[N-:3].[C:10]([O:14][P:15]([CH:22]([OH:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11].C[O-].[Na+].[Cl-].[Na+].O.CCOC(C)=O>CO>[N:1]([C:4](=[CH:27][C:26]1[CH:25]=[CH:24][C:23]([CH:22]([P:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16])[OH:31])=[CH:30][CH:29]=1)[C:5]([O:7][CH3:8])=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(=Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)N=[N+]=[N-]
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6.45 g (50 mmol) of ethyl α-azidoacetate and 1.64 g (5.0 mmol) of 4-[bis(tert-butoxy) -phosphorylhydroxymethyl)benzaldehyde 6 in MeOH (20 mL) at -78° C. was added a total of 7.4 mL (40 mmol) of NaOMe, 5.4M in MeOH, dropwise over 5 minutes. The mixture was stirred 5 minutes at -78° C. then an additional 1 hour at 0° C. The resulting light yellow suspension was subjected to an extractive work up (brine/EtOAc) to yield a light yellow crystalline solid, which was triturated with CHCl3 /pet. ether (35°-60° C.) to yield 7 as light yellow crystals, 1.26 g (57%), mp 111°-113° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([NH:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:11]1)=[O:39]
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 94 μl of pivaloyl chloride (0.76 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 154 mg (68% of theory)