Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:10]2=3)=[CH:5][CH:4]=1.[H-].[Na+].S(Cl)([Cl:34])=O.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C>[Cl:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:10]2=3)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(CO)cc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(CCl)cc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of the compound of Example 88 (130 mg, 0.32 mmol) in THF (2 mL) was added NaH (14 mg of 60% dispersion in oil, 0.35 mmol). DMF (0.5 mL) was added to aid solubility and the reaction was stirred for 1 h. Thionyl chloride (25 μL, 0.35 mmol) was added to the reaction mixture cooled in an ice-bath. The mixture was stirred in the ice-bath for 30 mins before quenching the reaction with water (20 mL) and basifying with NaHCO3(aq). The product was extracted into DCM (2×15 mL) and the combined DCM layers dried over MgSO4, filtered and concentrated in vacuo to give ethyl 7-(4-chloromethylphenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate LCMS (ES+) RT 3.97 minutes, 424 (M+H)+. To a solution of this compound in DMF (1 mL) was added 2-methylimidazole (13 mg, 0.16 mmol) and caesium carbonate (52 mg, 0.16 mmol) and the mixture heated at 80° for 3 h. DMF was removed in vacuo and the residue purified by column chromatography (silica, 40–100% EtOAc in isohexane followed by 5% MeOH in DCM) and also mass directed hpic to give the title compound as a solid (3 mg). δH (MeOH-d4) 7.47–7.27 (10 H, m), 7.06 (1H, d, J 1.4 Hz), 6.82 (1H, d, J 1.4 Hz), 6.50 (1H, d, J 9.6 Hz), 5.26 (2H, s), 4.00 (2H, q, J 7.1 Hz), 2.28 (3H, s), 0.99 (3H, t, J 7.1 Hz). LCMS (ES+) RT 2.53 minutes, 470 (M+H)+.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:41][O:42][CH2:43][C:44]1[N:45]=[C:46]([CH2:49][N:50]2[N:54]=[C:53]([NH2:55])[CH:52]=[N:51]2)[O:47][CH:48]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:41][O:42][CH2:43][C:44]1[N:45]=[C:46]([CH2:49][N:50]2[N:54]=[C:53]([NH:55][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[CH:52]=[N:51]2)[O:47][CH:48]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: COCc1coc(Cn2ncc(N)n2)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCc1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-phenyloxazole-4-carboxylic acid (WO 2009/077990, p. 113) (955 mg, 4.70 mmol) in CH2Cl2 (27 mL) was treated at rt with DMAP (143 mg, 1.17 mmol), HOBt (763 mg, 5.65 mmol), EDC (2.25 g, 11.75 mmol) and DIPEA (3.22 mL, 18.80 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(methoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (983 mg, 4.70 mmol) in CH2Cl2 (20 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (40 mL), the layers were separated and the org. phase was washed with water (40 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by crystallization for EA to give the title compound as a white solid: TLC: rf (4:6 hept-EA)=0.14. LC-MS-conditions 07: tR=0.84 min, [M+H]+=395.44.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28]>CO>[C:21]([C:20]1[CH:19]=[C:18]([N:17]2[C:8]3[CH:9]=[CH:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:7]=3[NH:6][C:27](=[O:28])[C:26]2=[O:30])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Temperature: 25 °C
Yield: 9.5 %

Procedure:
To an anhydrous tetrahydrofuran (18 mL) solution of 3-(1-amino-2-naphthylamino)benzonitrile (200 mg, 0.771 mmol) was added an anhydrous tetrahydrofuran (2 mL) solution of oxalyl chloride (66 μL, 0.771 mmol) under cooling in an ice-bath. The mixture was stirred under cooling in an ice-bath for 30 minutes and at room temperature for one hour. After addition of methanol (1 mL), the solvent was removed by evaporation under reduced pressure. The mixture was suspended by chloroform, and washed with a saturated aqueous sodium hydrogen carbonate solution. The precipitated solid was collected by filtration, and washed with water. The obtained solid was purified by silica gel chromatography (chloroform/methanol=9/1) to obtain the titled compound as a white powder (23 mg, yield 10%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:16]CC[N:13]2[CH3:17])[CH:7]=[N:8][CH:9]=1)[CH:2]=[CH2:3].[ClH:18].O.CO>CCOCC>[ClH:18].[CH2:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@@H:12]2[CH2:16][CH2:17][NH:13]2)[CH:7]=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cncc(OC[C@H]2CCCN2C)c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: C=CCc1cncc(OC[C@@H]2CCN2)c1

Procedure:
To a solution of 5-allyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine in Et2O was added hydrogen chloride (1.0 M in Et2O) carefully to afford the tittle compound: 1H NMR (D2O) δ 2.70 (q, 2H, J=8.5 Hz), 3.49 (d, 2H, J=6.5 Hz), 4.02-4.20 (m, 2H), 4.44 (d, 2H, J=4.5 Hz), 4.95 (m, 1H), 5.12-5.20 (m, 2H), 6.05 (m, 1H), 7.53 (s, 1H), 8.15 (s, 1H), 8.24 (d, 1H, J=2.0 Hz); MS (CI/NH3) m/z 205 (M+H)+. Anal. Calcd for C12H16N2O.2 HCl.0.2 H2O: C, 54.14; H, 6.82; N, 10.52. Found: C, 54.30; H, 6.82; N, 10.49. [α]25D -3.5 (c 0.63, MeOH).
Reaction SMILES: [CH2:1]1OCCOCCOCCOCCO[CH2:2]1.[OH-].[Na+].C([C:20]([CH2:33][CH3:34])(P(O)(O)=O)/[C:21](/[CH3:28])=[C:22](\CC)/[C:23]([O-:25])=[O:24])C.[CH3:35][C:36]([CH3:50])=[CH:37][CH2:38][CH2:39]/[C:40](/[CH3:49])=[CH:41]/[CH2:42][CH2:43]/[C:44](/[CH3:48])=C/C=O>C1(C)C=CC=CC=1>[CH3:28]/[C:21](/[CH:20]=[CH:33]/[CH:34]=[C:44](\[CH3:48])/[CH2:43][CH2:42]/[CH:41]=[C:40](\[CH3:49])/[CH2:39][CH2:38][CH:37]=[C:36]([CH3:35])[CH3:50])=[CH:22]\[C:23]([O:25][CH2:1][CH3:2])=[O:24]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Reactant: CC/C(C(=O)[O-])=C(/C)C(CC)(CC)P(=O)(O)O
Reactant: C1COCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(C)/C=C/C=C(\C)CC/C=C(\C)CCC=C(C)C
Temperature: 0 °C
Yield: 986.3 %

Procedure:
15-crown-5 (0.5 g, 0.1 equivalents, 2.27 mmol) was dissolved in 30 ml of toluene at room temperature, and added with 20 ml of 50% aqueous sodium hydroxide solution. To the solution, triethyl-3-methyl-4-phosphonocrotonate (7.87 g, 1.05 equivalents, 23.8 mmol) and then 5 ml toluene solution of farnesal (5.0 g, 22.7 ml) were added with stirring at 0° C. The mixture was stirred at room temperature for one hour. The organic and aqueous layers were separated, and the organic layer was washed with saturated ammonium chloride solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.4 g of the title compound (yield 98%, 2E:2Z=>99:1) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([OH:27])[C@H:18]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@@H:19]1[OH:20]>O1CCCC1>[C:1]([O:26][CH2:25][C@H:23]1[O:24][C@H:18]([CH2:17][OH:27])[C@@H:19]([OH:20])[C@@H:21]1[OH:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)c1ccccc1
Temperature: 25 °C

Procedure:
7.9 g. (6.5 ml., 56.3 mmol.) of benzoyl chloride and 5.7 g. (8.02 ml., 56.3 mmol.) of triethylamine were added to a suspension of 8.4 g. (51.2 mmol.) of 2,5-anhydro-D-mannitol in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for 5 hrs., allowed to cool to room temperature and evaporated at room temperature and 200 ml. of chloroform is added to the residue. The solids were removed by filtration and washed with chloroform and the chloroform filtrate and washings were combined and evaporated at reduced pressure. The residue was filtered through 200 ml. of silica gel utilizing chloroform and 5% methanol/chloroform to elute the dibenzoate and 5% methanol/chloroform and 10% methanol/chloroform to elute the monobenzoate. The fractions containing the monobenzoate (as indicated by thin layer chromatography) were combined and evaporated at reduced pressure to an uncrystallizable, very thick oil. The oil was distilled in a Kugelrohr apparatus at 135°-145° C. and 40μ. to obtain a thick, pale yellow oil (2.50 g.) [α]D =+46.191° (methanol).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][O:6][C@@H:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@@H:3]1[OH:21].[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O)(=O)C.C([C@@H]1CC=CCO1)(C1C=CC=CC=1)C1C=CC=CC=1>CC(C)=O>[CH:8]([C@H:5]1[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][CH2:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][CH:23]=[CH:24]3)[CH2:7][O:6]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O
Agent: C1=CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCc1ccc2[nH]ccc2c1

Procedure:
(2R,4S,5S)-5-amino-2-benzhydryl-tetrahydropyran-4-ol 31b (0.05 g, 0.18 mmol) was reacted with 1H-indol-5-carbaldehyde (0.03 g, 0.18 mmol), glacial acetic acid (0.01 g, 0.18 mmol) and NaCNBH3 (0.02 g, 0.35 mmol) (Procedure C) to give (2R,4S,5S)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol, (+)32b, 0.05 g (69%, [α]D=(+)70.9, c=1, Acetone).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH2:33]O)[CH:19]=[C:20]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:35])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:43])CC)C.O>ClCCl>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH2:33][F:43])[CH:19]=[C:20]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:35])[CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(-c4ccccc4CO)nn23)ccc1C(=O)NC1CC1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(-c4ccccc4CF)nn23)ccc1C(=O)NC1CC1
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of 329 mg (677 μmol) N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 220 in 13 mL dichloromethane at 3° C. were added 98 μL N-ethyl-N-(trifluoro-lambda4-sulfanyl)ethanamine. After stirring for 10 minutes, the solution was poured into water and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 28.6 mg (8%) of the title compound.
Reaction SMILES: [CH2:1]([CH2:8][N:9]=[C:10]([NH:12][N+:13]([O-])=O)[NH2:11])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5]>C(O)(=O)C.[Pt]=O>[CH2:1]([CH2:8][N:9]=[C:10]([NH:12][NH2:13])[NH2:11])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5]
Reactant: NC(=NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NNC(N)=NCCC[C@H](N)C(=O)O
Temperature: 100 °C
Reaction time: 60 h
Yield: 35 %

Procedure:
4.38 (20 mmol) NG -nitro-L-arginine (Sigma Chemicals) was dissolved in 25 ml of 15% aqueous acetic acid with 0.1 gm platinum oxide. The reaction was carried out at 40 psi H2 pressure and room temperature for about 60 hours. Catalyst was removed by filtration under argon, and the filtrate was rotary evaporated under reduced pressure to an oil. The oil was repeatedly dissolved in water and evaporated under vacuum and finally dissolved in 40 ml water. Analysis indicated 55% NG -amino-L-arginine and 45% L-arginine. The solution was adjusted to pH of 9.5 with NaOH and 5 mg arginase was added (1050 IU). The resulting solution was incubated at 37° C. overnight. After this treatment the solution contained NG -amino-L-arginine and L-orthinine but no L-arginine. The arginase was denatured by heating the solution to 100° C. for 5 to 10 minutes and removed by filtration. An aqueous solution of flavianic acid (6.28 gm in 100 ml) was added until the pH was about 3.8 and precipitate began to form. The solution was chilled to 40° C. overnight to complete precipitation of the product and the precipitate was collected by filtration (about 3.0 gm). The solid was redissolved in hot water (100 ml) by dropwise addition of 1 M NaOH. Addition to that solution of HCl to pH 3.8 caused formation of crystals of NG -amino-L-arginine monoflavianic acid salt. After chilling of the solution at 4° C. for 4 hours, the yellow crystals were collected by filtration and washed sequentially with absolute ethanol and ethyl ether. The product (2.4 grams) was pure NG -amino-L-arginine monoflavianic acid salt (C16H21N7O10S requires: C=38.2%; H=4.2%; N=19.5%. Found: C=38.4%, H=4.2%; N=19.5%). The monoflavianic acid salt was suspended in 100 ml of water at 100° C. and 10 grams of Dowex 1 (OH ), a strong base ion exchange resin, was added. After stirring at 100° C. for 5 hrs the supernatant was clear and all of the yellow flavianic acid was bound to the Dowex 1 resin. The resin was removed by filtration, and the clear filtrate was dried to an oil by rotary evaporation at reduced pressure. The oil was dissolved in 50 ml of ethanol and the ethanol was evaporated at reduced pressure. Addition and removal of ethanol was repeated again, and then 50 ml of ethyl ether was similarly added and removed. The solid residue was dried under high vacuum over P2O5 for 12 hours. The yield was 1.2 grams of pure (99.9+% pure) NG -amino-L-arginine (35% yield based on starting NG -nitro-L-arginine).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][CH:39]([NH:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH3:40]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][CH:39]([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)NCCCN
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCCNC(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N-(1-methylethyl)-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) 1.02 (m, 6 H), 1.68 (m, 2 H), 2.32 (m, 3 H), 2.46 (m, 1 H), 2.66 (m, 1 H), 2.82 (m, 1H), 3.11 (m, 1 H), 3.46 (m, 1 H), 6.35 (d, J=8.8 Hz, 1 H), 7.11 (m, 1 H), 7.24 (m, 2H), 7.46 (m, 2 H), 7.55 (m, 2 H), 8.02 (m, 1 H), 8.11 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17])=[O:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:14]([C:12]([O:11][CH3:10])=[O:13])[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2F)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-methoxycarbonyl-5-trifluoromethylaniline gave 2-chloro-5-fluoro-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidineamine. 1H NMR (CD3OD): δ 8.60 (s, 1H), 8.43 (s, 1H), 8.20 (d, 1H, J=3 Hz), 7.99 (s, 1H), 3.96 (s, 3H); 19F NMR (CD3OD): −18332, −18374; and −44259; LCMS: purity: 91%; MS (m/e): 350 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[NH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:34](=[O:35])[CH2:33][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]4[S:19][C:20]5[CH:26]=[C:25]([O:27][C:28]([F:31])([F:29])[F:30])[CH:24]=[CH:23][C:21]=5[N:22]=4)=[N:7][C:8]=3[CH:13]=2)=[O:15])[CH2:37][CH2:38]1
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN1CCN(C(=O)CN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCN(C)CC3)ccc21
Yield: 34.4 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide (45.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-1-(4-methyl-piperazin-1-yl)ethanone (40.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 593; and 1H NMR (DMSO-d6, 400 MHz): δ 8.49-8.46 (1H, m), 8.09 (1H, br. s), 7.95-7.93 (2H, m), 7.74 (1H, m), 7.53-7.50 (1H, m), 7.37-7.34 (1H, m), 4.37-4.36 (2H, m), 4.16-4.14 (2H, d), 3.74-3.71 (2H, t), 3.48-3.46 (4H, m), 3.24 (3H, s), 2.36-2.28 (4H, m), 2.20 (3H, s), —NH proton signal was not observed.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[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[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:64][N:65]1[CH2:70][CH2:69][N:68]([CH:71]2[CH2:76][CH2:75][CH:74]([NH2:77])[CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[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:77][C@H:74]5[CH2:73][CH2:72][C@H:71]([N:68]6[CH2:67][CH2:66][N:65]([CH3:64])[CH2:70][CH2:69]6)[CH2:76][CH2:75]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: CN1CCN(C2CCC(N)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(C)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for min before the addition of 4-(4-methylpiperazin-1-yl)cyclohexanamine (Intermediate 17) (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2 and Preparative—3) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-3-methoxybenzamide (white solid, 17 mg, 18%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-].[H][H]>[Pd].C1COCC1>[NH2:1][CH2:4][C@@H:5]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](CN)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate (2.1 g, 7.04 mmol, 1.0 equiv) and Pd/C (10%, ˜200 mg) were added to a flask. THF (30 mL) was added and the flask fitted with a gas inlet connected to a balloon of hydrogen gas. The flask was evacuated and back-filled with H2 from the balloon. This was repeated twice and the reaction mixture stirred for 17 h at ambient temperature. Analysis by LC/MS showed complete conversion to the desired amine. The catalyst was removed by filtration through a pad of Celite and the mixture evaporated. This provided 1.82 g (94%) of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[N+:28]([C:31]1[NH:32][CH:33]=[C:34]([CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:35]=1)([O-])=O.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[N:37]1([CH2:36][C:34]2[N:35]=[C:31]([NH:28][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:5])[NH:32][CH:33]=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: O=[N+]([O-])c1nc(CN2CCOCC2)c[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCOCC4)c[nH]3)c3nccnc23)c1F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 2 h at 70° C. and using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1). 4-(2-Nitro-1H-imidazol-4-ylmethyl)-morpholine (Step 23.1) was used instead of 2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. The title compound: ESI-MS: 511.1 [M+H]+; tR=3.21 min (System 1); TLC: Rf=0.34 (DCM/MeOH/NH3aq, 94:5:1).