Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31][C:32]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([C:8]3[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=4[N:9]=3)[CH2:12]2)=[O:33])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2c(Cl)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2c(Cl)cccc21

Procedure:
(R)-4-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (0.245 mmol, crude oil) (48A) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.319 mmol, 0.082 g) and N-methylmorpholine (1.47 mmol, 0.162 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.319 mmol, 0.121 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (48B) as a clear oil which was used without further quantification. ESI-ESI-MS: m/z 647.3 (M+H)+.
Reaction SMILES: N1C=CN=C1.Cl[Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1>ClCCl>[CH3:11][C:10]([Si:7]([CH3:9])([CH3:8])[O:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][O:15][CH3:14])[CH:19]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCOc1cccc(CO)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COCOc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
In a 100 ml round-bottomed flask (3-{[(methyloxy)methyl]oxy}phenyl)methanol (Intermediate 95, 3.5 g) was dissolved in dichloromethane (20 ml) to give a colourless solution. 1H-imidazole (1.700 g, 24.97 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (3.64 g, 24.14 mmol) were added. The reaction mixture immediately became a white suspension and was stirred at room temperature. After overnight stirring the reaction was completed. The reaction mixture was then quenched with 10 ml of water and diluted with 10 ml of dichloromethane. The phases were separated through a separating funnel. The organic phase was dried using a hydrophobic frit and evaporated under vacuum to give 6.0082 g of the crude product as a colourless oil which was purified via Biotage SP1 (with cyclohexane/EtOAc as eluents from 1:0 to 5:1 in 10 CV; then 5:1 for 5 CV; then from 5:1 to 1:1 in 5 CV; 100 g SNAP Silica column). Two fractions of the title compound were collected: 1.70 g of a colourless oil (purity: 93%) and 3.70 g of a colourless oil (purity: 98%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[O:14]1[CH2:18][C:17](=O)[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]1=2.Cl>O1CCCC1>[C:12]([CH2:11][C:17]1[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH:18]=1)#[N:13]
Reactant: O=C1COc2ccccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1coc2ccccc12
Temperature: 70 °C
Yield: 8.7 %

Procedure:
To a suspension of 27 gms (1.12 mole) of oil free sodium hydride in 400 ml of tetrahydrofuran (THF) was added dropwise a solution of 199.2 gms (1.12 mole) of diethylcyanomethylphosphonate in 400 mL of THF. After the H2 evolution had ceased, a solution of 150.1 g (1.12 mole) of 3-(2H)-benzo[b]-furanone in 1 L of THF was added. The solution was heated at 70° C. for 1.5 hours, cooled, and poured into 500 mL of 5% HCl, and washed with ether. The ether phase was washed with brine, dried (MgSO4), filtered and concentrated to give 15.4 g of a dark oil. The product was distilled at 110°-120° C./0.7 Torr Hg to give 116 g (66% yield) of a yellow oil which crystallized upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=[O:21])=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]#[N:12])=[C:9]([CH:10]=1)[C:8]([OH:11])=[O:21]
Reactant: O=C1C(=NO)Cc2ccc(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: N#CCc1ccc(Br)cc1C(=O)O

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-indan-1,2-dione 2-oxime and p-Toluenesulfonyl chloride to give 5-Bromo-2-cyanomethyl-benzoic acid. LC-MS: m/e: 238 (M−1).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH3:26])[N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:27]>CO.O>[CH3:26][C:13]1[N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:27])[C:11]=2[N:12]=1
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Reactant: N
Solvent: CO
Solvent: O
Product: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 150 °C

Procedure:
A suspension of 4-chloro-2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline (1.80 g, 4.55 mmol) in a solution of ammonia in methanol (7 M, 18 mL) in a high pressure vessel was heated at 150° C. for 14 hours. The vessel was allowed to cool to room temperature. A solid was isolated by filtration, washed with methanol, and purified by flash chromatography (silica gel, eluted with 10% methanol in dichloromethane) to provide a white solid. The solid was stirred in water (100 mL) for 1 hour, isolated by filtration, washed with water, and dried to yield 0.84 g of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 253-255° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:32]([O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[CH2:41])=[CH:38][CH:37]=1)(=[O:34])[CH3:33].C(N(CC)C(C)C)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:41]=[CH:40][C:39]1[CH:42]=[CH:43][C:36]([O:35][C:32](=[O:34])[CH3:33])=[CH:37][CH:38]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)Oc1ccc(C=Cc2ccccc2N)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-2-nitrobenzene (2.0 g), palladium(II) acetate (112 mg) and 2-(di-tert-butylphosphino)biphenyl (150 mg) in acetonitrile (20 ml) were sequentially added 4-acetoxystyrene (1.7 ml) and N,N-diisopropylethylamine (5 ml) under a nitrogen atmosphere, and the solution was stirred for 3 hours at 80° C. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), acetic acid 4-[2-(2-nitrophenyl)vinyl]phenyl ester (840 mg) was used according to an analogous synthetic method to Example 57 to provide the title compound (330 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[CH:11]1)(C)(C)C.[ClH:17].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[CH:11][N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:17]
Reactant: CC(C)(C)OC(=O)NCCn1cnc(I)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCn1cnc(I)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (6.154 g; 18.253 mmol) in DCM (200 ml) was added slowly 4N HCl in dioxane (91 ml; 364 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 1 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-imidazol-1-yl)-ethylamine was obtained as a colorless solid (5.690 g; 100%; presence of 2 eq. of HCl). LC-MS: tR=0.15 min.; [M+H]+=238.14 g/mol.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[C:10]([CH:13]=1)[CH2:11][NH2:12].[C:20]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:16][CH:17]([OH:19])[CH2:18]2)=[C:10]([CH:13]=1)[CH2:11][NH:12][C:29](=[O:30])[C@@H:28]1[CH2:32][CH2:33][CH2:34][N:27]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1cc(Cl)ccc1CN1CC(O)C1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(O)C1
Yield: 9.4 %

Procedure:
EDC (1.51 g, 7.87 mmol) was added to a stirred mixture of 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzylamine (1.19 g, 5.25 mmol), N-Boc-L-proline (1.13 g, 5.25 mmol) and HOAT (0.36 g, 2.62 mmol) in DMF (9 mL). After 16 h the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4)and evaporated. The residue was partitioned between EtOAc and 1M citric acid. The aqueous layer was made neutral with NaHCO3 and was extracted into CH2Cl2. The organic layer was evaporated and the residue was purified by chromatography on silica (ammonia saturated CHCl3/MeOH, 95:5) to give N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (210 mg) as a glass: MS: 424.5 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][C@@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 4.86 g (55.18 mmol) of (R)-(−)-3-hydroxytetrahydrofuran in 55 mL of anhydrous DCM (1M) was cooled to 0° C. with an ice bath. Then 8.5 mL (60.7 mmol, 1.1 eq.) of triethylamine and 4.8 mL (60.7 mmol, 1.1 eq.) of methanesulfonyl chloride were added successively. The reaction mixture was stirred for 2 hours at 0° C. and quenched with a saturated solution of sodium bicarbonate (70 mL). The aqueous layer was extracted with DCM (50 mL). Then the organic layers were washed with water (2×50 mL), brine (50 mL) and dried over sodium sulfate. After filtration and concentration in vacuo, a yellowish oil (7.93 g, 86.4%) was obtained corresponding to the methanesulfonic acid(R)-(tetrahydrofuran-3-yl)ester.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:16]1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[OH:1]
Reactant: O=C(O)c1cccnc1O
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cccnc1O
Reaction time: 28 h
Yield: 84 %

Procedure:
To a solution of 2-hydroxynicotinic acid (3-067-01) (50 g) in methanol (500 ml) were added conc. sulfuric acid (15 ml) and toluene (100 mL) at room temperature. After the reaction mixture was stirred for 28 h attached Dienstark reflux tube and neutralized with an aqueous potassium carbonate solution, the solvent was evaporated. To the residue were added aqueous saturated ammonium chloride solution and chloroform, and the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2-hydroxynicotinic acid methyl ester (3-067-02) (46 g, 84%) as a white solid.
Reaction SMILES: CC1C=CC(S([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([CH3:26])[CH2:21]4)[C:14]=3[C:13]([C:27]3[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=3)=[CH:12]2)(=O)=O)=CC=1.O.[OH-].[Li+].O>CC(O)C>[CH3:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:19]2[C:14]3[C:13]([C:27]4[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=4)=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(CO)c3)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C[C@H]1CCCN(c2ncnc3[nH]cc(-c4cccc(CO)c4)c23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (3-{7-[(4-methylphenyl)sulfonyl]-4-[(3S)-3-methylpiperidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)methanol (C16) from the previous step (<0.50 mmol) in 2-propanol (20 mL) was added lithium hydroxide monohydrate (0.42 g, 10 mmol) and water (3 mL) and the reaction mixture was stirred at room temperature for 18 hours. After concentration in vacuo, the residue was purified by preparative HPLC (Column: Waters XBridge; Mobile phase A: 0.1% ammonia in water; Mobile phase B: acetonitrile; Gradient: 44% to 60% B) to provide the product as a white solid. Yield: 130 mg, 0.403 mmol, 80% over two steps. LCMS m/z 323.4 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.46 (br s, 1H), 7.35-7.43 (m, 2H), 7.30 (br d, J=6 Hz, 1H), 7.23 (s, 1H), 4.67 (s, 2H), 3.89 (br d, J=13 Hz, 1H), 3.79 (br d, J=12 Hz, 1H), 2.58-2.69 (m, 1H), 2.27 (dd, J=12.0, 11.0 Hz, 1H), 1.62-1.71 (m, 1H), 1.30-1.52 (m, 3H), 0.87-1.01 (m, 1H), 0.60 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:48][C:39]([CH3:41])([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:40])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 81 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and cumylamine: yield 81%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:25][CH2:26][CH3:27])[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.O.[OH-].[Li+].Cl>CO.O.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2
Reactant: CCOC(Cc1ccc(NCCCCC(=O)N2CCOc3ccccc32)cc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(Cc1ccc(NCCCCC(=O)N2CCOc3ccccc32)cc1)C(=O)O
Yield: 67.9 %

Procedure:
Methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate (211 mg, 1 eq, 0.48 mmol) obtained in example 10, was hydrolyzed using lithium hydroxide monohydrate (60 mg, 3 eq, 1.44 mmol) in methanol-water at RT (takes 4-5 h). The reaction mixture was diluted with water, acidified (pH 3-4) with aqueous HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed (ethyl acetate and hexane→methanol/chloroform) to afford the title compound (139 mg, yield 68%) as viscous liquid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]1=[O:14])C.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][O:12][C:8]1[C:7](=[O:14])[N:6]([CH2:5][C:4]([NH:17][NH2:18])=[O:3])[CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: CCOC(=O)Cn1cccc(OC)c1=O
Solvent: CCO
Solvent: O
Product: COc1cccn(CC(=O)NN)c1=O
Yield: 83 %

Procedure:
As described for example 112a, (3-methoxy-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 83%). MS: m/e=220.1 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:26])[CH:22](Cl)[CH:23]=O)[CH3:19]>O1CCOCC1.CCOC(C)=O>[CH2:18]([O:20][C:21]([C:22]1[N:12]2[CH:13]=[C:14]([Br:15])[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])=[CH:10][C:11]2=[N:16][CH:23]=1)=[O:26])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Reactant: CCOC(=O)C(Cl)C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(CNC(=O)OC(C)(C)C)c(Br)cn12
Yield: 41 %

Procedure:
A solution of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (3.5 g, 11.6 mmol, prepared according to Example 1, Step 1.3) and freshly prepared 2-chloro-3-oxo-propionic acid ethyl ester (8.97 g, 59.6 mmol, prepared according to a patented procedure U.S. Pat. No. 5,559,158-A1) in dioxane (60 mL) was stirred at RT for 14 h. The reaction mixture was diluted in AcOEt (400 mL) and washed with a 2.0 M aqueous Na2CO3 solution (2×200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→2:8) to yield the title compound (1.31 g, 4.83 mmol, 41%) as a light yellow solid. MS: 398 [M+1]+; HPLC: AtRet=1.85; TLC: RF 0.47 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([C:11]#[C:12][C:3]2[C:4]([NH2:9])=[N:5][C:6]([NH2:8])=[N:7][C:2]=2[Cl:1])=[CH:14][CH:15]=1
Reactant: Nc1nc(N)c(I)c(Cl)n1
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2c(N)nc(N)nc2Cl)cn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 850 mg (3.1 mmol) 6-chloro-5-iodo-pyrimidine-2,4-diamine, 2.2 g (19 mmol) 5-ethynyl-2-amino-pyridine, 59 mg (0.31 mmol) CuI, 218 mg (0.31 mmol) PdCl2(PPh3)2 and 21 mL triethylamine in 25 mL dry DMF. Yield after purification by RP-HPLC: 720 mg (88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[H][H].C(O)C.O>[CH2:1]([O:3][C:4]([C@@H:6]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)N[C@@H](C)C(=O)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Temperature: 20 °C
Yield: 67.6 %

Procedure:
N-(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine [(1S/1R)=9.0] (10.0 g, 34 mmoles) was added to 105 ml of 7% (w/w) water-containing ethanol containing 1.9 N sulfuric acid. Thereto 50% (w/w) water-containing 5% Pd--C (5.0 g) was added and the catalytic reduction was carried out in hydrogen atmosphere (atmospheric pressure) under the conditions of an inner temperature of about 20° C. and an agitation power of a range from 0.5 to 1 kW/m3 (amount of sulfuric acid based on substrate: 6 equivalents). Supply of hydrogen was stopped at the time when hydrogen is absorbed in 90% and somewhat more of the required amount. And then, the atmosphere was rapidly replaced with nitrogen to stop the reaction. Pd--C was rapidly removed by filtration and the Pd--C cake was conscientiously washed with 10 ml of 7% (w/w) water-containing ethanol and 5 ml of water. After 30 ml of water was added to the resulting filtrate, the filtrate was neutralized (pH 4.5) by slowly adding dropwise an aqueous 30% (w/w) sodium hydroxide solution. The filtrate was concentrated at the inner temperature of a range from 40° to 60° C. under reduced pressure, and then concentrated under reduced pressure with appropriately adding water to obtain slurry with replacing with water. The content of ethanol in the slurry was 3% (w/w), the content of sodium sulfate was 9% (w/w) and the pH was 5.0. After cooling to an inner temperature of 20° C., the crystal was filtered and washed with water in a 2-fold amount of the cake. The resulting crystal was vacuum-dried (30 mmHg to 0.1 mmHg) at a range from 40° to 60° C. to obtain N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (6.3 g, 23 mmoles). The yield was 75%. HPLC purity: 99.3% (w/w), the content of N-(1(R)-ethoxycarbonyl-3-phenylpropyl)-L-alanine: not detected, the content of N-(1-ethoxycarbonyl-3-cyclohexylpropyl)-L-alanine: 0.1% (w/w), the content of N-(1-carboxy-3-phenylpropyl)-L-alanine: less than 0.1% (w/w), residue on ignition: 0.1% 35 (w/w).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC(C)([O-])C.[Na+].Br[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1>C1COCC1.C(OCC)(=O)C>[CH3:52][O:51][C:48]1[CH:49]=[CH:50][C:45]([NH:1][C:2]2[C:7]3[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:46][CH:47]=1
Reactant: Cn1c(=O)[nH]c2cccc(N)c21
Reactant: COc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2cccc3[nH]c(=O)n(C)c23)cc1
Temperature: 60 °C
Yield: 41.8 %

Procedure:
A mixture of 0.183 g (1.12 mmol) of 7-amino-1-methyl-1,3-dihydrobenzimidazol-2-one, 0.037 g (0.11 mmol) of biphenyl-2-yl-dicyclohexylphosphane, 0.237 g (2.47 mmol) of sodium tert-butoxide and 0.041 g (0.045 mmol) of tris(dibenzylidineacetone)dipalladium in 6 mL of THF was treated with 0.14 mL (1.12 mmol) of 4-bromoanisole and heated to 60° C. for 18 h. The crude reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and purified by flash chromatography eluting with a 97% dichloromethane/methanol mixture to give 0.126 g (42%) of the title compound as a tan powder.