Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:23]#[N:24])[CH:18]=3)[N:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:25]1([C:31]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:32]2[CH:36]=[N:35][C:34]([CH2:37][CH2:38][C:39](O)=[O:40])=[N:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:23]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:10]([NH:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][CH2:37][C:34]3[N:35]=[CH:36][N:32]([C:31]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:33]=3)[CH:3]=1)=[O:11])[NH:21][C:20]2=[O:22])#[N:24]
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(N)c3)[nH]c(=O)c2c1
Reactant: O=C(O)CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
A solution of N-[(3-aminophenyl)methyl]-6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 45 (120 mg, 0.376 mmol), 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoic acid obtained in Reference Example 25 (152 mg, 0.396 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (106 mg, 0.554 mmol) and 1-hydroxybenzotriazole (74.9 mg, 0.554 mmol) in DMF (5 mL) was stirred at 40° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and water was added to residue. The resulting solid was collected by filtration, washed with water and IPE, and dried to give 6-cyano-4-oxo-N-{[3-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoyl}amino)phenyl]methyl}-3,4-dihydroquinazoline-2-carboxamide as a white powder (232.0 mg, 86%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[C:19]([OH:24])(=[O:23])[CH:20]([CH3:22])[CH3:21].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>C1COCC1>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]([OH:29])[C:20]([CH3:22])([CH3:21])[C:19]([OH:24])=[O:23]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)C(O)c1ccccc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
To a solution of diisopropylamine (3.31 mL, 23.22 mmol) in THF (5 mL) was added n-BuLi/hexane (9.29 mL, 23.22 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 5 min and then stirred in ice bath for 20 min. The reaction mixture was added dropwise with a solution of isobutyric acid (1.055 mL, 11.61 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and 60° C. for 2 h. The flask was recooled to 0° C., and a solution of 2-fluorobenzaldehyde (1.441 g, 11.61 mmol) in THF (5 mL) was added dropwise. Then the solution was allowed to warm to rt and stirred for 16 h. The reaction was quenched with 1 N HCl until pH˜3 and extracted with EtOAc. The combined organic layers were washed with 1 N NaOH. The combined basic washes were acidified with HCl and extracted with EtOAc. Then organic phase was washed with sat. NaCl, dried over anhydrous MgSO4, and concentrated to yield 3-(2-fluorophenyl)-3-hydroxy-2,2-dimethylpropanoic acid (1.5 g, 60.9% yield) as Cap N-9. 1H NMR (400 MHz, DMSO-d6) ppm 7.50 (td, J=7.5, 1.8 Hz, 1H), 7.32 (tdd, J=7.7, 5.4, 1.8 Hz, 1H), 7.22 (td, J=7.5, 1.0 Hz, 1H), 7.14 (ddd, J=10.5, 8.3, 1.3 Hz, 1H), 5.28-5.11 (m, 1H), 3.33 (br. s., 1H), 1.06-0.97 (m, 3H), 0.93 (d, J=2.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[OH:27])[CH3:2].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:27][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:36])[CH3:35]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(C)=O
Reaction time: 24 h

Procedure:
2β-Ethoxy-3α-hydroxy-5α-pregnane-11,20-dione (500 mg.) in dry methylene chloride (5 ml.) at 0° was treated with pyridine (2.0 ml.) and acetic anhydride (2.0 ml.). After 24 hours, methylene chloride was added, and the solution was washed with dilute hydrochloric acid and with water. It was then dried over sodium sulphate and evaporated to an oil. The title compound (350 mg.) was obtained as a colourless foam, [α]D + 132°.
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])[C:4](=[NH:8])[O:5]CC.[O:17]1CCC[CH2:18]1>>[F:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([F:16])[C:9]=1[CH:3]1[O:2][C:18](=[O:17])[NH:5][C:4]1=[O:8]
Reactant: CCOC(=N)C(O)c1c(F)cccc1F
Reactant: C1CCOC1
Agent: Cl
Product: O=C1NC(=O)C(c2c(F)cccc2F)O1

Procedure:
By the procedure of Example 89, ethyl 1-hydroxy-1-(2,6-difluorophenyl)methanecarboximidate hydrochloride (12 g., 0.048 mole) in 500 ml. of tetrahydrofuran was converted to crude product. The crude was recrystallized from about 60 ml. of isopropanol to yield purified 5-(2,6-difluorophenyl)oxazolidine-2,4-dione [5.8 g., 57%; m.p. 196°-198° C., m/e 213 ir (KBr) 3175, 1812, 1739, 1361, 1152 cm-1 ].
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[C@@H:41]2[N:37]([CH2:38][CH2:39][CH2:40]2)[CH2:36][C:35]2[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](O)=[O:49])[CH:44]=[N:45][C:34]=2[NH:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>CO>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:48](=[O:49])/[CH:47]=[CH:46]/[C:43]1[CH:44]=[N:45][C:34]2[NH:33][C:32](=[O:31])[C@@H:41]3[N:37]([CH2:38][CH2:39][CH2:40]3)[CH2:36][C:35]=2[CH:42]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Reactant: CNCc1cc2ccccc2n1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Yield: 35 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (R)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.19 g, 35%) was prepared as a tan powder: [α]25D −173.9° (c 1.00, methanol); 1H NMR (300 MHz, DMSO-d6) δ 12.50 (br s, 1H), 11.27 (s, 1H), 8.83-8.74 (m, 1H), 8.32-8.25 (m, 1H), 7.65-7.60 (m, 1H), 7.51-7.32 (m, 3H), 7.15-6.96 (m, 2H), 6.43-6.18 (m, 1H), 5.07-4.86 (m, 2H), 4.47-4.21 (m, 3H), 3.79-2.88 (m, 9H), 2.09-1.88 (m, 3H); MS (ESI) m/e 430 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:16][CH3:17])[CH:10]([CH3:15])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:18].CO.O.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([CH2:16][CH3:17])[C@H:10]([CH3:15])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:18]
Reactant: CCC1C(c2ccc(N)c(O)c2)=NNC(=O)C1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC[C@H]1C(c2ccc(N)c(O)c2)=NNC(=O)[C@H]1C

Procedure:
1.10 g (4.45 mmol) 6-(4-amino-3-hydroxy-phenyl)-5-ethyl-4-methyl-4,5-dihydro-2H-pyridazin-3-one are separated by RP (xBridge, MeOH/H2O/TFA).
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.Br[CH2:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:22]O>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[O:21])[CH2:14][S:10][C:8]1[NH:7][C:6]2[CH:11]=[CH:12][C:3]([CH3:22])=[CH:4][C:5]=2[N:9]=1)[CH3:20]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nc2cc(C)ccc2[nH]1
Yield: 92 %

Procedure:
A solution of 5-methoxy-2-benzimidazolethiol (200 mg, 1.11 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (5 mL) and acetone (2 mL) was shaken at room temperature for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(5-Methyl-1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (300 mg, 92%). 1H-NMR (D3COD, 300 MHz) δ (ppm): 7.19 (br. s, 1H), 6.75 (br. s, 1H), 6.69 (dd, J=2.3 Hz, J=8.8 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 4.29 (br. s, 1H), 3.93 (br. s, 1H), 3.69 (s, 3H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]([CH2:5][C@@H:6]1[O:18][C@H:17]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)[C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:34][C:35](=[CH:39][O:40][CH3:41])[C:36](Cl)=[O:37].P(O)(O)([O-])=O.[K+]>C(Cl)Cl>[CH3:34][C:35](=[CH:39][O:40][CH3:41])[C:36]([N:1]([CH2:5][C@@H:6]1[O:18][C@H:17]([CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)[C:2]([NH2:4])=[O:3])=[O:37]
Reactant: COC=C(C)C(=O)Cl
Reactant: NC(=O)NC[C@H]1C[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC=C(C)C(=O)N(C[C@H]1C[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
In 32.2 ml of methylene chloride was dissolved 2.3 g of 1-ureido-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol followed by addit ion of 9.2 ml of pyridine. Then, 1.67 g of 2-methyl-3-methoxypropenoyl chloride was added and the mixture was stirred at room temperature overnight. This reaction mixture was poured in 5% aqueous solution of monopotassium phosphate followed by extraction with ethyl acetate. The organic layer was washed with 5% aqueous monopotassium phosphate solut ion thrice, saturated aqueous sodium hydrogen carbonate solution once, and saturated aqueous sodium chloride solution once in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (chloroform→1% methanol/chloroform) to provide 2.3 g of the desirable compound as pale-yellow oily substance.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH2:15])[CH:7]=[C:8]([S:11]([OH:14])(=[O:13])=[O:12])[CH:9]=2)[CH:4]=[C:3]([S:16]([OH:19])(=[O:18])=[O:17])[CH:2]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:15][C:6]1[C:5]2[C:10](=[CH:1][CH:2]=[C:3]([S:16]([O-:19])(=[O:18])=[O:17])[CH:4]=2)[CH:9]=[C:8]([S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2ccc(S(=O)(=O)O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(S(=O)(=O)[O-])cc2ccc(S(=O)(=O)[O-])cc12

Procedure:
A 45.0 g amount of (62.5%) 1-naphthylamine-3,7-disulfonic acid is suspended in 200 ml of water and 30 ml of 5 N sodium hydroxide is added to it. The solution is warmed and absolute ethyl alcohol is added until a cloudy precipitate forms. The solution is cooled and the solid is collected by filtration and is washed with 85% ethyl alcohol, ethyl alcohol and ether. The product is dried in vacuo at 110° C. to give 21.0 g of 4-amino-2,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][C:23]1=[O:32]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][C:23]2=[O:32])[CH2:13][CH2:12]1
Reactant: O=C1CCc2ccccc2N1CCCCBr
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Product: Cl
Product: O=C1CCc2ccccc2N1CCCCN1CCC(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
from 7-chloro-3-(piperidin-4-yl)-1H-indole and 1-(4-bromobutan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 253-254° C. 1H NMR (DMSO-d6): 1.55-1.65 (m, 2H); 1.75-1.85 (m, 2H); 2.05-2.25 (m, 4H); 2.55 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 6.95-7.05 (m, 2H); 7.15-7.30 (m, 5H); 7.70 (d, 1H); 10.60 (broad s, 1H); 11.30 (s, 1H). MS m/z: 436 (MH+), 289.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])([O-:12])=[O:11].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>COCCOC.CCOC(C)=O>[CH3:9][NH:8][C:4]1[CH:3]=[C:2]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])[N:7]=[CH:6][N:5]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CNc1cc(Nc2ccccc2[N+](=O)[O-])ncn1
Temperature: 90 °C
Yield: 35 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (1 g, 7 mmol), 2-nitro-phenylamine (965 mg, 7 mmol), Brettphos (279 g, 0.35 mmol) and tBuONa (2 g, 21 mmol) in DME (50 mL) was heated to 90° C. for 1 hour under nitrogen atmosphere. The reaction was concentrated, and the residue was purified by flash chromatography on silica eluting with DCM:EtOAc=10:1-4:1 to obtain the title compound (600 mg, yield: 35%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.94 (d, 3H), 4.99 (bs, 1H), 5.82 (s, 1H), 7.04 (t, 1H), 7.60 (t, 1H), 8.21 (d, 1H), 8.33 (s, 1H), 8.75 (d, 1H), 9.91 (s, 1H); MS (ESI): 246 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:21]([C:22]4[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=4)[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:21]([C:22]4[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]5[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=5)=[CH:24][CH:23]=4)[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(-n2c(-c3ccc(C4CCCCC4)cc3)nc3cccnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(-c4ccc(C5CCCCC5)cc4)nc4cccnc43)cc2)cc1
Yield: 42.6 %

Procedure:
4-[2-(4-Cyclohexylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.37 g, 0.93 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.377 g, 0.93 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.317 g, 0.396 mmol).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([CH3:24])=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH3:23])[CH:14]=2)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[O:25]1CCOCC1>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([CH:24]=[O:25])=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH3:23])[CH:14]=2)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cc2cc(OC)c(OC)cc2nc1C)OCC
Reactant: C1COCCO1
Product: CCOP(=O)(Cc1cc2cc(OC)c(OC)cc2nc1C=O)OCC

Procedure:
SeO2 (0.56 g, 5.06 mmol) was added to a solution of 3-(diethylphosphonomethyl)-6,7-dimethoxy-2-methylquinoline (1.79 g, 5.06 mmol) in dioxane (25 ml). The mixture was refluxed for 75 min, filtered and concentrated. The remaining oil was purified by chromatography to give 1.48 g 3-(diethylphosphonomethyl)-6,7-dimethoxyquinoline-2-carboxaldehyde.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:16](=[O:17])[C:15]([C:18]([O:20]CC)=O)=[CH:14][N:6]3[CH2:7][C:8](=[O:13])[N:9]([CH3:12])[C:10]([CH:11]=1)=[C:5]23.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(#N)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:18]([C:15]2[C:16](=[O:17])[C:4]3[C:5]4[N:6]([CH:14]=2)[CH2:7][C:8](=[O:13])[N:9]([CH3:12])[C:10]=4[CH:11]=[C:2]([I:1])[CH:3]=3)=[O:20])=[CH:26][CH:25]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)N(C)C(=O)C2
Solvent: CC#N
Product: CN1C(=O)Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(I)cc1c32

Procedure:
A mixture of ethyl 9-iodo-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate (Preparation 22, 400 mg) is stirred at 180° C. in 4-chlorobenzylamine (2.0 mL) for 1 h. The mixture is cooled and diluted with acetonitrile to give 412 mg of the title compound. Physical characteristics: M.p. 278-283° C.; 1H NMR (DMSO-d6) δ3.38, 4.55, 5.21, 7.35, 7.39, 7.69, 8.18, 8.76, 10.12. Anal. Found: C, 47.43; H, 3.01; N, 8.32; Cl, 7.14.
Reaction SMILES: B(F)(F)F.[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][Cl:8].B(F)(F)F.O.O.[C:22](Cl)([CH3:25])([CH3:24])[CH3:23]>O>[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][Cl:8].[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:12][CH:11]=1)[CH2:7][Cl:8]
Reactant: CC(C)(C)Cl
Agent: CC(CCl)Cc1ccccc1
Agent: FB(F)F
Solvent: O
Product: CC(CCl)Cc1ccc(C(C)(C)C)cc1

Procedure:
BF3 is passed for 30 minutes into a mixture of 84 parts by weight of 2-methyl-3-phenyl-propyl chloride and 50 ml of BF3.2H2O at room temperature. 56 parts by weight of tert.-butyl chloride are then added dropwise at room temperature. The mixture is refluxed for 4 hours and is then allowed to cool; the crude product is introduced into water and extracted with chloroform. The organic phase is separated off, washed with water, dried over Na2CO3 and distilled. 30 parts by weight of 2-methyl-3-phenyl-propyl chloride, boiling point 105° C./16 mm Hg, and 45 parts by weight of 2-methyl-3-(p-tert.-butylphenyl)-propyl chloride, boiling point 80°-81° C./0.02 mm Hg, are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[NH:5][CH2:4][C:3]#[N:2])[CH:18]=[CH2:19]
Reactant: N#CCN
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)NCC#N
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a suspension of 110 g of aminoacetonitrile hydrochloride in 1.2 l of acetonitrile were added at 20° C. 121.5 g of triethylamine. The mixture was cooled in an acetone-ice bath and 144.7 g of allyl chloroformate were added slowly, the temperature being maintained below 20° C. Subsequently, 121.5 g of triethylamine were added at such a rate that the temperature did not rise above 20° C. The mixture was stirred at 20° C. for 2 h and then, the solids were removed by filtration. The mother liquor was concentrated in vacuo and the oily residue was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated potassium hydrogen sulfate solution, saturated potassium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residual oil was distilled in vacuo to yield 132.6 g of cyanomethyl-carbamic acid allyl ester as a colorless oil, b.p. 100° C./0.07 mbar.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][NH:3]1.Br[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>C(#N)C.CCCCC.CCOCC>[CH2:16]([N:3]1[CH:4]=[CH:5][C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([C:8]#[N:9])[C:2]1=[O:1])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: N#Cc1c(-c2cccs2)cc[nH]c1=O
Reactant: CC(C)CCBr
Solvent: CCOCC
Solvent: CCCCC
Solvent: CC#N
Product: CC(C)CCn1ccc(-c2cccs2)c(C#N)c1=O
Yield: 60 %

Procedure:
According to Scheme 21: The title compound was prepared according to Example 1 Step 2 from 1,2-dihydro-2-oxo-4-(thiophen-2-yl)pyridine-3-carbonitrile (1 eq, 0.50 mmol, 0.10 g) and 1-bromo-3-methylbutane (1.5 eq, 0.70 mmol, 0.10 g). Reaction conditions: 17 hours at 60° C. in acetonitrile (10 mL). The crude product was purified by chromatography over silicagel (AIT Flashsmart prepacked column SiO2, cyclohexane/AcOEt 80/20) and recrystallized in pentane/Et2O yielding the title compound (88 mg, 0.30 mmol, 65%) as a yellow solid. M.p.: 123° C.; LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=4.29 min; MS m/z (CI) [MH]+=273; 1H NMR (300 MHz, DMSO-d6) δ 0.92 (d, J=5.6 Hz, 6H), 1.48-1.63 (m, 3H), 3.90-4.02 (m, 2H), 6.72 (d, J=7.2 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.96-8.04 (m, 2H), 8.08 (d, J=7.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([C:32](C)=[CH2:33])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:6].[OH-].[Na+].OO.C1C[O:46][CH2:45]C1>>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([CH2:32][CH2:33][CH2:45][OH:46])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]1=[O:31])[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:6]
Reactant: C1CCOC1
Reactant: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)C(CCNC(=O)c1ccc(F)c(F)c1)C1(CCCO)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A cold (0° C.) solution of tert-butyl α-[2-[(3,4-difluorobenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (1.62 g, 3.07 mmol) in dry THF (10 mL) is treated with monochloroborane methylsulfide complex (640 μL, 6.14 mmol). The ice bath is removed, and after 4.5 h, 3N NaOH (7.4 mL, 22.1 mmol) is added dropwise, followed by 30% H2O2 (2.5 mL). The solution is stirred for 1 hour at room temperature and then for 1 hour at 50° C. After cooling to room temperature and dilution with saturated NH4Cl (5 mL) and H2O (15 mL), the product is extracted into EtOAc (3×50 mL). The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 1.6 g of a yellow gel. The material is purified by silica gel chromatography (75 g SG; 75% EtOAc/hexane) to provide 713 mg (43%) of the title compound as a white, amorphous solid: