Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:16][CH:17]([OH:19])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A solution of (S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (12 mg, 0.028 mmol) in 3:1 THF/MeOH (4 mL) was cooled to 0° C. NaBH4 (2.1 mg, 2 equiv) was added. After 15 min, the mixture was warmed to rt slowly. After stirring 1.5 h, LC-MS found the reaction completed. The mixture was quenched by water (2 mL), concentrated, and purified by preparative HPLC to afford (6S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one (4.4 mg, 36%). LC-MS (3 min) tR=1.68 min, m/z=458, 460 (M+Na). 1H NMR (CDCl3) 7.36-7.21 (m, 3H), 7.12-6.96 (m, 4H), 6.83 (m, 1H), 5.63 (m, 1H), 2.93 (m, 1H), 1.51 (d, 3H), 1.17 (d, 3H).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:6]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:5]1=2)(=[O:3])[CH3:2].[ClH:43]>O1CCOCC1.CCOCC>[ClH:43].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:6]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(Br)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2cc(Br)ccc2OC)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 72 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-1-(5-bromo-2-methoxybenzyl)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (35.5 mg, 55.2 μmol) in 4 M HCl in dioxane (276 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-1-(5-bromo-2-methoxybenzyl)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (23.0 mg, 72%) as a white solid. MS m/z 542/544 (MH)+.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:14][C@@H:13]([O:15]CC2C=CC=CC=2)[CH2:12][C@@H:11]1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[C].[Pd].C(O)C>[C:1]([O:9][C@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][C@@H:11]1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cn1nccc1[C@H]1C[C@H](O)C[C@@H]1OC(=O)c1ccccc1
Yield: 90.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 106b by using the (1S*,2R*,4S*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl benzoate (297 mg, 0.789 mmol) prepared in Example 107a, palladium carbon (5%; 300 mg) and ethanol (3.0 mL), to yield the title compound (205 mg, 91%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:33](O)[CH2:34][CH2:35][OH:36].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:33][CH2:34][CH2:35][OH:36]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C)c2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 5-methyl-3-(3-methylphenylsulfonyloxy)phenol (560 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a colorless oil (605 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.41 (s, 1H), 6.36 (s, 1H), 4.13 (t, J=7.2 Hz, 2H), 3.81 (m, 2H), 2.43 (s, 3H), 2.24 (s, 3H), 1.96 (m, 2H), 1.61 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](I)[CH:19]=[CH2:20].O>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]([CH2:20][CH:19]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Br
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)C(C)(C)C)c1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-(3-bromo-6-chloro-2-pyridinyl)-2,2-dimethylpropanamide (2.305 g, 7.907 mmol) in DMF (40 ml) at 0° C. under argon was treated with sodium hydride (0.696 g, 17.395 mmol) and then allowed warm to rt over 0.25 h, stirred at rt for 0.25 h and then treated with allyl iodide (1.61 ml, 17.395 mmol) and stirred at rt for 1 h. The reaction was then treated with water (10 ml), concentrated to approximately 5 ml, treated with more water (200 ml) and extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), filtered, evaporated and the residue chromatographed (0-20% ethyl acetate:Hexane) to give the product as a yellow oil which solidified to an off white solid (5.324 g, 67%).
Reaction SMILES: C(O)(C)(C)C.C(O)C.[BH4-].[Na+].[CH:11]1([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([N:21]=[CH:22]N(C)C)[N:16]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=3[F:33])[C:15]2=[O:34])[CH2:13][CH2:12]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH:11]1([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([NH:21][CH3:22])[N:16]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=3[F:33])[C:15]2=[O:34])[CH2:12][CH2:13]1
Reactant: CN(C)C=Nc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCO
Product: CNc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Under a nitrogen atmosphere, to t-butanol-ethanol [2:1 (volume ratio), 250 ml] was added sodium borohydride (6.41 g), and the mixture was stirred at room temperature for 1 hr. Under water-cooling, N′-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine 76 (50.0 g) was added, and the mixture was stirred for 2.5 hrs. Under water-cooling, water (225 ml) and 10% aqueous citric acid solution (175 ml) were successively added dropwise, and the mixture was stirred for 3 hrs. The precipitated crystals were collected by filtration and dried to give crude crystals (34.5 g, LC purity 91%) of 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52, which were used for the next reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28](O)=[N:29][CH:30]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=2)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C(c2ccc(F)c(F)c2)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)cn2)C(c2ccc(F)c(F)c2)C1
Temperature: 25 °C

Procedure:
A mixture of 1 g (3 mmol) (3SR,4SR)-3-(3,4-Difluoro-phenyl)-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester, 0.59 g (4.5 mmol) 5-chloro-2-hydroxy pyridine, 1.1 g (4.8 mmol) di-tert-butyl azodicarboxylate and 2.42 g (5 mmol) triphenylphosphine (polymer bound) in 70 mL THF was stirred at room temperature over night. the mixture was filtered through decalite and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to afford after evaporation of the product containing fractions 1.2 g (91%) of the title compound as viscous colorless oil. MS (m/e): 439.1 [(M+H)+].
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[C:17](=O)[N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[CH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl>O1CCOCC1>[CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[CH2:17][N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[CH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(nc3n(Cc4ccccc4)c(=O)cc(O)n23)n(C)c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)cc(O)n3c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 395 g (1.12 moles) of 9-benzyl-1,3-dimethyl-6-hydroxy-pyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione in 10.5 liters of dry 1,4-dioxan, add 68.1 g (3.14 moles) of lithium borohydride in portions. Maintain the reaction temperature at 20°-25° C. by controlling the rate of addition and by use of a cooling bath as needed. Stir the mixture at room temperature for 0.5 hour, then reflux for 18 hours. Remove a portion of the solvent under reduced pressure, and purge the system with nitrogen as the vacuum is released. Allow the residue to cool; then add 4.5 liters of chloroform. To the resultant mixture, cautiously add dropwise 1.1-liters of water. Stir the mixture at room temperature until two clear phases result. Add 3N hydrochloric acid portionwise to bring the pH to 4-5. Separate the layers, and extract the aqueous phase with two 1.1-liter portions of chloroform. Wash the combined extracts with three 1.1 liter volumes of water, and dry over anhydrous sodium sulfate. Filter off the drying agent, and remove volatiles from the filtrate under reduced pressure. Crystallize the residue from methanolethyl acetate to obtain title compound (I) as a solid with mp 176°-182° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=O.O>CS(C)=O>[Cl:14][C:15]1[C:16]2[CH:17]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[S:3][C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl thioglycolate (11.3 ml) was added under nitrogen to a stirred solution of triethylamine (45 ml) in dimethyl sulphoxide (160 ml), then the mixture was stirred at ambient temperature for 30 minutes. A solution of 2-chloro-6-fluorobenzaldehyde (20 g) in dimethyl sulphoxide (80 ml) was added then the mixture was stirred at 95° C. for 4.66 hours, allowed to stand at ambient temperature for 18 hours and poured into water (1600 ml). The resulting solid was collected by filtration, washed with water (3×100 ml), and dried in vacuo to give methyl 4-chlorobenzo[b]thiophene-2-carboxylate (22.4 g) as an off-white solid, m.p. 84-86° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[OH:27].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:27][C:21]2[C:20]([F:19])=[CH:25][CH:24]=[CH:23][C:22]=2[F:26])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1c(F)cccc1F
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2c(F)cccc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 49.6 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.17 g of 2,6-difluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 4-(2-butynyloxy)-6-(2,6-difluorophenoxy)pyrimidine (the present compound (33)), m.p.: 79.8° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1
Reactant: CSC(=C[N+](=O)[O-])NCC1CCOC1
Reactant: C1CCNC1
Solvent: CC#N
Product: O=[N+]([O-])C=C(NCC1CCOC1)N1CCCC1
Temperature: 25 °C

Procedure:
A mixture comprising 1.2 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene, 1.5 ml of pyrrolidine and 15 ml of acetonitrile was stirred at room temperature for an hour. The reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/acetone=1/1) to obtain 0.92 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-(1-pyrrolidinyl)-2-nitroethylene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH2:16][C:15]3[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:23][N:24](C)C=O.[C-]#N.[Na+]>C(Cl)(Cl)Cl>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH2:16][C:15]3[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1)#[N:24]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(Br)cc1)C2
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(C#N)cc1)C2

Procedure:
2-(4-Bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone (8.00 g., 0.02 mole), cuprous cyanide (3.94 g., 0.04 mole) and dimethylformamide (100 ml.) are heated at reflux for 8 hours, added to warm sodium cyanide solution (3 g. in 400 ml. water), extracted with benzene, the benzene solution dried over anhydrous magnesium sulfate, then concentrated in vacuo to give an oily residue. Chromatographing with chloroform on silica gel gives 1.13 g. of 2-(4-cyanophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone melting at 161°-163° C. after crystallization from benzene:hexane, 2:1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[C:31]1([CH2:37][CH2:38][N:39]([CH2:44][CH:45]2[CH2:47][O:46]2)[S:40]([CH3:43])(=[O:42])=[O:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([CH2:37][CH2:38][N:39]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:44][CH:45]([OH:46])[CH2:47][N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Reactant: CS(=O)(=O)N(CCc1ccccc1)CC1CO1
Solvent: CCO
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(O)CN(CCc2ccccc2)S(C)(=O)=O)CCN(CC(=O)OCC)CC1

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 5.11 g (20 mmol) of N-(2-phenylethyl)-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2f), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (Eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO>C(O)C.C(Cl)(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[S:8][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cccnc1
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1csc(-c2cccnc2)n1
Temperature: 70 °C
Yield: 71.4 %

Procedure:
A solution containing thionicotinamide (30 g, 217.1 mmol) in ethanol (540 mL) was treated with ethyl bromopyruvate (30.3 mL, 241.4 mmol), heated at 70° C. for 3 hours, cooled to 25° C., concentrated and partitioned between chloroform and saturated NaHCO3. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with chloroform and then with 15% methanol in chloroform containing 1% ammonium hydroxide to give the product (36.3 g, 71% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.C1C(=O)N([Cl:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Cl:26]
Reactant: CCOC(=O)Cc1ccc(N)c(OCC2CC2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cc(Cl)c(N)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and the volatiles removed in vacuo. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.[C:6]1([S:12]([OH:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([S:12]([CH:5]2[CH2:4][CH2:3][CH2:2][O:1]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1=COCC1
Reactant: O=S(O)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,3-dihydrofuran (1.40 g, 19.97 mmol) and benzene sulfinic acid (3.12 g, 21.97 mmol) in methylene chloride (80 mL) was stirred at 25° C. for 2 h. The reaction was then transferred to a separatory funnel and washed with a saturated aqueous sodium carbonate solution (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was then recrystallized using diethyl ether/petroleum ether to afford 2-benzenesulfonyl-tetrahydro-furan as a white solid: mp 55.9–56.8° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8]Br.BrCC1C=C(Cl)C(CC2C=C(C(C)C)[C:23](=O)[NH:24]N=2)=C(Cl)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8][C:23]#[N:24]
Reactant: OCc1cc(Br)c(CBr)c(Br)c1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CBr)cc2Cl)n[nH]c1=O
Product: N#CCc1c(Br)cc(CO)cc1Br
Yield: 78 %

Procedure:
This compound was prepared by a similar method to that described in Example 14, Step 5 except that (3,5-dibromo-4-bromomethyl-phenyl)-methanol (58) was used in place 6-(4-bromomethyl-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (54). The product was purified by flash chromatography using silica gel eluted with a gradient of 3:1 to 1:1 hexanes:ethyl acetate. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 2,6-dibromo-4-hydroxymethyl-phenyl)-acetonitrile (59) (78%) as a yellow solid; EI(+)-HRMS m/z calcd for C9H7Br2NO (M 302.8894, found 302.8881. MW=304.9702, Exact Mass=302.8894
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:28]4[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.C[Si](C)(C)[C:42]#[C:43][C:44]1([CH3:48])[CH2:47][O:46][CH2:45]1>CCOC(C)=O.[Cu]I.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:34][C:29]1[C:28]([C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[N:16]4)[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:42]#[C:43][C:44]5([CH3:48])[CH2:47][O:46][CH2:45]5)[CH:3]=4)[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C#Cc2cnc3c(c2)[C@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A vial was charged with (5)-tert-butyl 3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.181 g, 0.333 mmol), copper(i) iodide (0.013 g, 0.067 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.024 g, 0.033 mmol). The vial was flushed with Ar (g), then DMF (1.665 mL), DIPA (0.712 mL, 5.00 mmol), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.201 mL, 0.999 mmol) were added in sequence. The reaction was heated to 90° C. and stirred for three hours. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-50% EtOAc:Hex) to afford (S)-tert-butyl 7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as a yellow solid. MS m/z=559.2. Calc'd for C30H27FN4O4S: 558.62.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1>>[O:33]=[S:30]1(=[O:34])[CH2:31][CH2:32][N:27]([C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:28][CH2:29]1
Reactant: O=S1(=O)CCNCC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)nn1
Yield: 73 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using thiomorpholine-S,S-dioxide instead of aminomethylcyclopropane, to the title compound (131 mg, 73%) which was obtained as an off white solid. MS: m/e=447.1 [M+H]+.