Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[C:1]1([C@H:7]2[N:11]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][CH:9]([CH2:16][O:17][C:21]3[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)N1CC(CO)O[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)N1CC(COc2ncccc2C#N)O[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (S)-2-phenyl-3-tert. butyl-5-hydroxymethyl- oxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethyl- formamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred four hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform extract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, (S)-2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:42][O:43][CH2:44][CH2:45][NH2:46]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:46][CH2:45][CH2:44][O:43][CH3:42])[N:4]=1
Reactant: COCCN
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of Example C2 (0.15 g, 0.36 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.11 g, 0.43 mmol), stirred at RT overnight, treated with 2-methoxyethanamine (0.5 mL) and stirred at RT for 4 h. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-N-(2-methoxyethyl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (100 mg, 63%). MS (ESI) m/z: 448.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[N:10][N:9]2[C:12]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[O:31])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[CH3:29])[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[CH:7]=1)=[O:5])C.[OH-].[Li+]>O1CCOCC1>[C:41]([O:40][C:38]([N:35]1[CH2:34][CH2:33][N:32]([C:30]([C:12]2[N:9]3[N:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]3=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])=[O:31])[CH2:37][CH2:36]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C(=O)O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 102.3 %

Procedure:
The compound of step 10 (1.680 g, 2.80 mmol) was dissolved in 20 ml of dioxane and a 1 M aqueous solution of lithium hydroxide (4.30 ml, 4.30 mmol) was added. After stirring for 45 min at room temperature, the dioxane was evaporated under reduced pressure and 50 ml of water were added. The mixture was acidified to pH 2 with 5 N hydrochloric acid. The solid was filtered off, rinsed with water and dissolved in EA (100 ml). The solution was washed with water (50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to give 1.64 g of the title compound which was directly used in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:11](=[O:12])[C:10]([CH3:15])([CH3:14])[CH3:9])[CH:7]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73.6 %

Procedure:
This compound was prepared as reported by K. S. Gudmundsson et al, Synthetic Communications 1997, 27 (5), 861-870: To a stirred solution of 2-amino-4-chloropyridine (0.723 g, 5.62 mmol) in anhydrous pyridine (2.8 ml) was dropwise added trimethylacetyl chloride (1.02 g, 8.46 mmol). The reaction mixture was stirred at room temperature for 4.5 h under argon, then partitioned between ethyl acetate (70 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×30 ml), and the combined organics were washed with saturated aqueous NaHCO3 (40 ml), brine (50 ml), dried (Na2SO4), and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 50 g isolute silica column. Elution with 20% ethyl acetate in hexanes and 25% ethyl acetate in hexanes afforded the title compound as a white solid (0.880 g, 74%); 1H-NMR (250 Mz, DMSO-d6) 1.24 (s, 9H, C(CH3)3), 7.25 (dd, J=1.91 Hz, 5.36 Hz, 1H, 5-H), 8.17 (d, J=1.87 Hz, 1H, 3-H), 8.34 (d, J=5.35 Hz, 1H, 6-H), 10.09 (s, 1H, CONH); LC-MS (ESI, m/z) 6.91 min—213, 215 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[Se:15][C:14]=1[C:22]([NH2:24])=[O:23].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:19])[CH3:20])[Se:15][C:14]=1[C:22]([NH2:24])=[O:23])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1cc(Nc2ncnc3ccc(N)cc23)c(C(N)=O)[se]1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Nc2ncnc3ccc(NC(=O)CCl)cc23)c(C(N)=O)[se]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 3-(6-aminoquinazolin-4-ylamino)-5-tert-butylselenophene-2-carboxamide (510 mg, 1.31 mmol) in THF (10 mL) was added a solution of chloroacetyl chloride (0.105 mL, 1.31 mmol) in THF (1.0 mL) at rt. The mixture was stirred at rt for 30 min (solid separated). The solution was poured into ice cold water and stirred for 15 min. The separated solid was filtered, washed with water and dried to give the product as a yellow color solid (540 mg, 80%). This crude product was further chromatographed and recrystallized from chloroform-methanol. Mp 262-264° C.; IR (KBr) vmax 3437, 3109, 2961, 1706, 1652, 1608, 1575, 1541, 1464, 1386, 1355, 1311, 1241, 1137, 1086, 858, 834, 790 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 12.79 (1H, s, exchangeable with D2O), 10.83 (1H, s, exchangeable with D2O), 8.83 (1H, s), 8.73 (1H, s), 8.60 (1H, br s), 8.01-8.03 (1H, m), 7.89 (1H, d, J=8.8 Hz), 7.68 (2H, br s), 4.41 (2H, s), 1.47 (9H, s); 13C NMR (100 MHz, DMSO-d6): δ 167.9, 167.2, 164.9, 154.9, 153.2, 146.3, 145.5, 137.2, 128.7, 126.7, 121.1, 115.2, 113.1, 110.0, 43.3, 36.5, 32.2; LC-MS (negative ion mode): m/z 462, 464, 466 (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:18])([F:17])[C:9](=O)[CH2:10][C:11]([O:13]CC)=O.C(O)(=O)C(O)=O.[CH2:25]([NH:27][NH2:28])[CH3:26]>C(O)C>[CH2:25]([N:27]1[C:11]([OH:13])=[CH:10][C:9]([C:8]([F:7])([F:17])[F:18])=[N:28]1)[CH3:26]
Reactant: CCNN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1nc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 45.0 g of potassium carbonate and 50.0 g (272 mmol) of ethyl 4,4,4-trifluoroacetoacetate in 300 mL of ethanol was cooled with a salt/ice bath to about 0° C. and to this ethylhydrazine oxalate (44.9 g, 299 mmol) was added with a spatula with stirring. After 45 min (minutes) at about 0° C., the mixture was allowed to warm to ambient temperature and stir for 1 hour. It was then heated to reflux overnights The mixture was concentrated by evaporation under reduced pressure and the residue was diluted with dichloromethane and water. The product only partially dissolved and seemed to be distributed in both phases. The layers were separated and the aqueous layer was extracted with dichloromethane and filtered. The solids obtained on filtration were extracted with dichloromethane. The dichloromethane layers and extracts were combined, washed with water (2×200 mL), and dried and the volatiles were allowed to evaporate overnight. All of the solids were combined to obtain the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:47])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][C:26]=1[O:34][CH2:35][CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:47])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][C:26]=1[O:34][CH2:35][CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC(C=O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ccccc12
Temperature: -65 °C
Reaction time: 4.5 h

Procedure:
To a 65° C. solution of lithium aluminum hydride (0.37 ml, 1M in diethyl ether) in diethyl ether (5 mL) was added a solution of 3-[4-carbamoyl-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.20 g, 0.34 mmol) in diethyl ether (5 mL). The reaction was stirred at −65° C. for 4.5 hours. The reaction was then diluted with ethyl acetate (100 mL) and washed with 10% potassium hydrogen sulfate (25 mL) and saturated sodium chloride (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 3-[4-carbamoyl-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester as a clear oil. MS(APCI) m/z 525.1(M−H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: CN
Product: CNC(=O)c1cnc(/C=C/c2c(-c3ccc(F)cn3)noc2C)s1
Yield: 77 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using methylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (66 mg, 77%) which was obtained as a yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=345.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=1>CN(C=O)C>[NH2:25][C:21]1[N:22]=[C:23]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[C:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7]2)[CH:24]=[CH:19][N:20]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CN(C)C(=O)c1n[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-N,N-dimethyl-1H-indazole-3-carboxamide (95%, 450 mg, 1.59 mmol) in DMF (10 mL) was added NaH (60% dispension in mineral oil) (60 mg, 1.02 mmol) at 0° C. Mixture was stirred at rt for 10 mins before addition of 4-chloropyrimidin-2-amine (413 mg, 3.19 mmol). The mixture was stirred at 65° C. overnight. The mixture was quenched by addition of water (10 mL). The mixture was extracted with EtOAc (2×15 mL). The combined organics washed with water (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Trituration with DCM:heptane (4:1) gave the desired product. The filtrate was re-filtered. The solids were combined to give the title compound; 1H NMR (250 MHz, DMSO) delta 3.11 (3H, s), 3.32 (3H, s), 7.08 (1H, d, J=5.48 Hz), 7.19 (1H, d, J=3.35 Hz), 7.58 (1H, dd, J=8.68, 1.68 Hz), 7.95 (1H, d, J=8.53 Hz), 8.34 (1H, d, J=5.63 Hz), 9.18 (1H, d, J=1.22 Hz); LC-MS: m/z=+362.8 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][N:6]=[C:5]([Cl:11])[CH:4]=1.[CH3:12][Si:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C:19]1=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:11][C:5]1[N:6]=[CH:7][C:8]2[CH2:9][C:20]3([CH2:2][C:3]=2[CH:4]=1)[C:21]1[C:22](=[N:23][CH:24]=[CH:25][CH:26]=1)[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:28])([CH3:12])[CH3:29])[C:19]3=[O:27]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: Clc1cc(CBr)c(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cnc(Cl)cc3C2)c2cccnc21
Reaction time: 21 h

Procedure:
To a solution of 4,5-bis(bromomethyl)-2-chloropyridine from Step D (254 mg, 0.85 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (226 mg, 0.86 mmol, described in Intermediate 4) in DMF (8 mL) was added cesium carbonate (455 mg, 1.40 mmol). After 21 h, the reaction mixture was poured into H2O (60 mL) and extracted with EtOAc (2×60 mL). The organic layer was washed with brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=402 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N+:6]([C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[NH2:16])([O-:8])=[O:7].C(=O)(O)[O-].[Na+]>O>[CH3:5][O:4][C:2]([NH:15][C:13]1[CH:12]=[CH:11][C:10]([NH2:16])=[C:9]([N+:6]([O-:8])=[O:7])[CH:14]=1)=[O:3]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Methyl chloroformate (34 g) was added dropwise with stirring to a mixture of 2-nitro-p-phenylenediamine (50 g), sodium bicarbonate (44.5 g) and water (700 ml). The temperature was maintained at 5° C. during the addition by means of external cooling. After the addition was complete the mixture was allowed to warm to room temperature and the stirring was continued for two hours. The solid was filtered off and recrystallised from isopropanol to give 4-methoxycarbonylamino-2-nitroaniline (50 g), m.p. 171°-172° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[CH3:35][NH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cccnc1
Product: CN[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 102.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=458.0 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[F:17][C:18]([F:52])([F:51])[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:22]=[C:21]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]3[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=3)[CH:36]=2)[N:20]=1>C1COCC1>[CH2:1]([NH:8][S:47]([C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([C:37]2[CH:36]=[C:35]([C:21]3[N:20]=[C:19]([C:18]([F:17])([F:51])[F:52])[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[N:22]=3)[CH:40]=[CH:39][N:38]=2)[CH:42]=1)(=[O:48])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCc1ccccc1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of benzylamine (0.32 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.49 g, 85%). MS (ISP) 614.8 [(M+H)+]; mp 202.5° C.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[BH4-].[Na+].O>C(O)C>[I:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(I)ccc2Sc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1Cc2cc(I)ccc2Sc2ccccc21
Reaction time: 8 h

Procedure:
12.0 g of 10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-one are suspended in 100 ml of ethanol and the mixture is treated with 6 g of sodium borohydride. The mixture is stirred overnight, then treated with water and extracted with ether. The organic phase is washed with water until neutral, dried over magnesium sulphate and evaporated. The 10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-ol obtained is recrystallised from ether; melting point 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:16](CC4C=CC(OC)=CC=4)[N:15]=3)=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:16][N:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2nc(CCc3cnc4ccc(Cl)cc4n3)nc2N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2ncc(CCc3n[nH]c(N4CCCC4)n3)nc2c1
Yield: 17.7 %

Procedure:
7-chloro-2-(2-(1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl)ethyl)quinoxaline (17 mg, 37.9 μmol, Eq: 1.00) was stirred in trifluoroacetic acid (173 mg, 117 μl, 1.51 mmol, Eq: 40) with anisole (81.9 mg, 82.7 μl, 757 μmol, Eq: 20) at 120° C. overnight. The mixture was made basic by addition of sodium hydroxide 2N aq. and extracted three times with 1,2-dichloromethane, dried over magnesium sulfate, filtered and evaporated. The crude material was applied on silica gel and purified by column chromatography to give 7-Chloro-2-[2-(5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-yl)-ethyl]-quinoxaline (2.2 mg, 17.7%) as off-white solid. MS: m/z=329.12 (M+H+)
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13]>O1CCCC1>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of propan-1-amine (2.36 g, 0.04 mol) in tetrahydrofuran (100 mL) at 0° C. was added triethylamine (4.05 g, 0.04 mol) and 2-nitrobenzene-1-sulfonyl chloride (8.88 g, 0.04 mol) in several portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 4 hours, filtered and concentrated to afford the product 2-nitro-N-propylbenzenesulfonamide (9.18 g, yield 93.9%). 1H NMR (400 MHz, CDCl3) δ ppm 8.11-8.16 (m, 1H), 7.84-7.89 (m, 1H), 7.74-7.79 (m, 2H), 5.26 (s, 1H), 3.05-3.10 (t, 2H, J=6.4 Hz), 1.51-1.60 (m, 2H), 0.89-0.92 (t, 3H, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[C:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])[CH3:41]>>[C:40]([N:43]1[CH2:48][CH2:47][N:46]([C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]3[C:8](=[O:30])[N:7]([CH2:6][C:5]4[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:4]=4)[CH2:14][CH2:13][CH2:12][NH:11][C:10]=3[N:15]=2)[CH2:45][CH2:44]1)(=[O:42])[CH3:41]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Yield: 75.2 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (70.0 mg, 75%).