Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][N:34]([CH3:50])[CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42](C(O)=O)=[CH:41]2.CCN=C=NCCCN(C)C>CC(N(C)C)=O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22]([C:42]3[NH:43][C:44]4[C:40]([CH:41]=3)=[CH:39][C:38]([O:37][CH2:36][CH2:35][N:34]([CH3:50])[CH3:33])=[CH:46][CH:45]=4)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
A suspension of 14 (0.20 g, 0.47 mmol) in cooled (0° C.) dioxane (5 mL) was saturated with HCl, allowed to warm to r.t. over 2 h and evaporated. 5-[2-(Dimethylamino)ethoxy]-1-H-indole-2-carboxylic acid hydrochloride (0.13 g, 0.47 mmol) [Milbank et al., J. Med. Chem., 1999, 42, 649], EDCI (0.27 g, 1.42 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 20 h. The mixture was partitioned between EtOAc and 5% NaHCO3 solution. The aqueous layer was extracted with EtOAc (×3). The EtOAc extracts were dried (brine, Na2SO4). Flash chromatography (Alumina, EtOAc/MeOH; 49:1, then 9:1) gave 2-[(2-{[5-(benzyloxy)-1-(chloromethyl)-1,2-dihydro-3H-pyrrolo[3,2-f]quinolin-3-yl]carbonyl}-1H-indol-5-yl)oxy]-N,N-dimethylethanamine (17b) (0.22 g, 84%) as a yellow solid: mp 176–179° C.; 1H NMR [(CD3)2SO]δ 11.68 (s, 1 H), 8.79 (dd, J=4.1, 1.5 Hz, 1 H), 8.41 (dd, J=8.6, 1.5 Hz, 1 H), 8.29 (s, 1 H ), 7.56 (m, 3 H), 7.40 (m, 4 H), 7.17 (d, J=2.3 Hz, 1 H ), 7.11 (d, J=1.5 Hz, 1 H), 6.92 (dd, J=9.0, 2.4 Hz, 1 H), 5.32 (s, 2 H), 4.82 (dd, J=10.7, 9.6 Hz, 1 H), 4.58 (dd, J=10.9, 2.1 Hz, 1 H), 4.32 (m, 1 H), 4.05 (t, J=5.7 Hz, 2 H), 4.04 (m, 1 H), 3.93 (dd, J=11.2, 6.9 Hz, 1 H), 2.65 (t, J=5.8 Hz, 2 H), 2.23 (s, 6H); 13C NMR [(CD3)2SO]δ 160.3, 154.5, 153.0, 147.3, 142.3, 137.4, 136.7, 131.6, 131.3, 130.6,128.4, 127.9, 127.7, 127.4, 125.1, 122.4, 116.2, 116.0, 113.1, 105.5, 103.1, 102.0, 70.0, 66.9, 66.2, 57.8, 54.9, 47.7, 45.5, 40.7.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.[CH2:20]([Li])CCC.CI.O>CCCCCC>[CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH:8]([CH3:20])[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: [Li]CCCC
Reactant: CN1CCN2c3ccccc3Cn3cccc3C2C1
Solvent: O
Solvent: CCCCCC
Solvent: CI
Product: CC1c2ccccc2N2CCN(C)CC2c2cccn21

Procedure:
To the solution of 2.5 g of 2-methyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine (Example 1) in 25 ml of tetrahydrofran is added 4.5 ml of 2.45 molar n-butyl lithium in hexane at room temperature while stirring under nitrogen. The pale yellow solution rapidly becomes cherry-red and the temperature rises about 7°. The mixture is stirred for an additional 45 minutes, whereupon it is treated with methyl iodide until the color of the solution is discharged. After stirring for a further 30 minutes the mixture is poured into 100 ml of water, and the product is extracted with diethyl ether. The extract is washed successively with water and brine, evaporated and the residual oil chromatographed on silica gel, using 2% methanol-methylene chloride as eluent, to yield the 2,10-dimethyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine which is converted to its mono maleate melting at 157°. The identical product is also obtainable according to the methods of Examples 1 and 15 by selecting o-nitro-α-methylbenzyl chloride or bromide respectively.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.N1C=CC=CC=1.[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>O1CCCC1.C(OCC)(=O)C>[CH3:26][C:21]1[CH:20]=[C:19]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[CH:24]=[CH:23][C:22]=1[NH:25][C:34](=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1N
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc(NCc2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
To a solution of (4-amino-3-methylphenyl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (500 mg, 1.31 mmol) in dry tetrahydrofuran (10 mL) at 0° C. was added pyridine (159 mL, 1.97 mmol) followed by butyryl chloride (164 μL, 1.58 mmol) dropwise. After 5 minutes, the reaction mixture was allowed to warm to room temperature, and stirring was continued for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed with 2 N HCl, saturated aqueous sodium bicarbonate twice, and brine, and was then dried over magnesium sulfate. Solvents were evaporated in vacuo and the residue was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid. After 30 minutes at room temperature the mixture was evaporated to dryness, the residue was dissolved in ethyl acetate (10 mL), the solution was washed twice with saturated aqueous sodium bicarbonate, twice with water, and was then dried over sodium sulfate. Evaporation of the solvents and recrystallization of the residue from ethyl acetate:heptane gave the title compound as a colorless solid (226 mg, 49%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.S1C=CN=C1C(O)(C#C)C.[CH3:36][C:37]1[O:41][N:40]=[C:39]([C:42]([OH:46])([C:44]#[CH:45])[CH3:43])[CH:38]=1>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:45]#[C:44][C:42]([C:39]4[CH:38]=[C:37]([CH3:36])[O:41][N:40]=4)([OH:46])[CH3:43])[CH:10]=3)[C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: C#CC(C)(O)c1nccs1
Product: Cc1cc(C(C)(O)C#Cc2ccc3c(C(=O)N4CCOCC4)nn(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by procedure described in Example 61-c, by substituting 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide with 4-{6-bromo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: 1H NMR (500 MHz, DMSO) delta 1.86 (3H, s), 2.42 (3H, s), 3.63-3.70 (2H, m), 3.70-3.80 (4H, m), 3.89-3.97 (2H, m), 6.41 (1H, s), 6.58 (1H, s), 7.08 (1H, d, J=5.36 Hz), 7.16 (2H, br. s.), 7.44 (1H, dd, J=8.35, 1.26 Hz), 8.02 (1H, d, J=8.35 Hz), 8.35 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+474.4 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][S:15][CH2:16][CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Nn1nc(N2CCSCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(N2CCSCC2)c2ccccc2c1=O

Procedure:
The product from Example 91B and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.30 (d, J=7.9 Hz, 1H), 7.84-8.02 (m, 3H), 7.05-7.19 (m, 3H), 3.73 (s, 2H), 2.83-2.87 (m, 4H); MS (APCI+) M/Z 417 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][CH2:9][C@H:10]([NH:19]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C)C=O>[C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][CH2:9][C@H:10]([NH2:19])[C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCOCC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@H](N)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
[(S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-morpholin-4-yl-4-oxobutyl]carbamic acid tert-butyl ester (172 mg, 0.338 mol) obtained in Step 1 above was dissolved in N,N-dimethylformamide (1.5 ml), and then piperidine (84 μl) was added thereto. After the solution was stirred at room temperature for 30 minutes, the solvent was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=20:1) to yield ((S)-3-amino-4-morpholin-4-yl-4-oxobutyl)carbamic acid tert-butyl ester (95 mg) as a colorless oily material.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH:12](=[O:16])[CH:13]([CH3:15])[CH3:14].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:14][C:13]([CH3:15])([C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH:12]=[O:16]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CC(C)C=O
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C=O)[C@@H](C[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from (E)-(2-nitrovinyl)benzene and isobutyraldehyde according to the general procedure. The enantiomeric ratio were determined by HPLC with Chiralpak OD-H column at 210 nm (2-propanol:hexane=15:85), 1 mL/min, tmajor=19.7 min, tminor=13.9 min, [α]D20=−4.3 (c=1.6, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(/C=C/C(=O)O)ccc1F
Yield: 96.7 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (30 g, 195 mmol) in pyridine (134 ml) and Piperidine (4.12 ml) was added malonic acid (30.4 g, 292 mmol) at room temperature. The reaction mass was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was acidified with 1.5N HCl solution. The precipitated solid was filtered washed with pet ether to get crude compound (37 g, 97%) as white solid. The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ ppm 12.37 (s, 1H), 7.59-7.55 (d, J=16 Hz, 1H), 7.53 (s, 1H), 7.26-7.22 (m, 2H), 6.59-6.55 (d, J=16 Hz, 1H), 3.89 (s, 3H); MS: MS m/z 195.0 (M+−1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>[OH-].[Na+].[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N:21]1([CH2:20][CH2:19][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OCc1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: OCc1ccc(OCCN2CCCCC2)cc1
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
4-hydroxybenzyl alcohol (6.2 g, 0.0.05 mol) was dissolved in aqueus sodium hydroxide (SN, 30 mL). Toluene (30 mL) was added followed by 1-(2-chloroethyl) piperidine hydrochloride (9.29 g, 0.05 mol) and benzyltriethylammonium bromide (0.3 g). The reaction mixture was heated with vigorous stirring for 1.5 h. The layers were separated, the aqueous layer was extracted with toluene (2×15 mL). Combined organic extracts and organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated on a rotary evaporator to give 8.725 g (75%) of alcohol (3a) as a yellowish brown oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[S:32][C:31]([Cl:33])=[N:30][CH:29]=4)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C([O-])(=O)C.[Na+].O>ClCCl.C(OCC)(=O)C>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[S:32][C:31]([Cl:33])=[N:30][CH:29]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc(Cl)s3)nc12)C(=O)N1CCC(C#N)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[C@@H](NC(=O)c1c[nH]c2ncc(-c3cnc(Cl)s3)nc12)C(=O)N1CCC(C#N)CC1
Yield: 26.1 %

Procedure:
2-(2-Chlorothiazol-5-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (39 mg, 0.063 mmol) was dissolved in 0.8 mL of dichloromethane and then stirred in an ice bath. Trifluoroacetic acid (0.4 mL) was added slowly and the ice bath was removed. The reaction was stirred for 2.5 h and then cooled in ice bath. Sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in 4 mL of absolute ethanol, sodium acetate (104 mg, 1.27 mmol) was added and the mixture was stirred at 60° C. for 20 h. The reaction was cooled, and water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Purification by reverse phase chromatography afforded 8 mg (26%) of 2-(2-chlorothiazol-5-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide. MS: (M+Na)+=509.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([NH:27][C:28](=[O:30])[CH3:29])[C:17]([CH3:31])=[C:16]([Cl:32])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:32][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([NH:27][C:28](=[O:30])[CH3:29])[C:17]=1[CH3:31]
Reactant: CC(=O)Nc1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1c(C)c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (22 mg, 0.11 mmol), N-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]acetamide (32 mg, 0.10 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.20 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H21ClFN6O (M+H)+: m/z=439.1. found: 439.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:44]1([C:50]2[CH:54]=[C:53]([CH2:55][N:56]3[CH2:61][CH2:60][CH:59]([CH2:62][NH2:63])[CH2:58][CH2:57]3)[O:52][N:51]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:63][CH2:62][CH:59]2[CH2:58][CH2:57][N:56]([CH2:55][C:53]3[O:52][N:51]=[C:50]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:54]=3)[CH2:61][CH2:60]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Cl
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.7 %

Procedure:
To a solution of 4-chloro-3-methoxybenzoic acid (65 mg) in dichloromethane (4 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (67 mg), 1-hydroxybenzotriazole hydrate (58 mg), and diisopropylethylamine (0.25 mL). The mixture was stirred at room temperature for five minutes and then the hydrochloride salt of the compound prepared in Example 9 (100 mg) was added. The reaction mixture was stirred at room temperature for 16 hours. The organic phase was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1, then ethyl acetate) to obtain the title compound (70 mg) having the following physical data.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13](=[O:26])[CH2:14][O:15][C:16](=[O:25])[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=O)C1C=CC=CC=1>CCO.Cl.[Pd]>[NH2:11][CH:12]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13](=[O:26])[CH2:14][O:15][C:16](=[O:25])[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24]
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(N)CC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
2,6-Dimethyl-benzoic acid 3-benzyloxycarbonylamino-4-tert-butoxycarbonyl-2-oxo-butyl ester, 110, (11.3 g, 24.1 mmol) is dissolved in a solution of EtOH (400 mL) and 1 N HCl (29 mL), treated with 10% Pd/C (500 mg) and stirred under a hydrogen atmosphere for 4 h. The solution is filtered and concentrated to yield 7.6 g of the desired product as an HCl salt that was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: O=S1(=O)CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCS(=O)(=O)CC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(1,1-dioxo-thiomorph-olin-4-yl)-nicotinamide was prepared starting from intermediate E and thiomorpholine-1,1-dioxide. MS calcd. for C26H23ClN4O4S [(M+H)+] 523.1, obsd. 523.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:19])([F:18])[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][CH:11]=1.[OH2:20].[OH-].[Na+]>C(OCC)C>[F:7][C:8]([F:19])([F:18])[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:20])=[CH:12][CH:11]=1
Reactant: O
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccc(OC(F)(F)F)cc1

Procedure:
A solution of lithium aluminium hydride in diethyl ether (1.0M, 69.4 ml) was added dropwise to a stirred solution of 4-(trifluoromethoxy)benzonitrile (6.0 g) in diethyl ether (120 ml) over 15 minutes. Water (2.66 ml), 10% sodium hydroxide solution (2.66 ml) and water (7.98 ml) were then added successively, dropwise. The precipitated solid was filtered off and washed with diethyl ether. The filtrate and washings were combined and evaporated under reduced pressure to give 4-(trifluoromethoxy)benzyl alcohol, N.M.R. in deuteriochloroform: δ2.3 (1H,s), 4.65 (2H,s), 7.2 (2H,d), 7.35 (2H,d).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([O:13][CH3:14])[N:3]=1.Cl.[Cl:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]([F:36])[C:29]=2[F:37])=[CH:20][C:18]=1[NH2:19].C(N(CC)C(C)C)(C)C.O>C(#N)C.C(OCC)(=O)C>[Cl:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]([F:36])[C:29]=2[F:37])=[CH:20][C:18]=1[NH:19][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([O:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(OC)nc1Cl
Reactant: COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cnc(OC)nc1Nc1cc(OCc2c(OC)ccc(F)c2F)c(OC)cc1Cl
Yield: 17.6 %

Procedure:
A mixture of ethyl 4-chloro-2-methoxypyrimidine-5-carboxylate (0.22 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline hydrochloride (0.4 g) and N,N-diisopropylethylamine (0.37 mL) in acetonitrile (3 mL) was heated at reflux for 1.5 hours. The reaction mixture was poured into water. To the mixture was added ethyl acetate, and the insoluble material was collected by filtration. The collected solids were washed with water and ethyl acetate, and dried under reduced pressure to give ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-methoxypyrimidine-5-carboxylate (91 mg). To this material were added methanol (2 mL) and 1 mol/L aqueous sodium hydroxide solution (0.9 mL), and the mixture was stirred at 50° C. for 1 hour. To the mixture was added tetrahydrofuran (1 mL), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature. To the mixture was added 1 mol/L hydrochloric acid (1.0 mL), and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-methoxypyrimidine-5-carboxylic acid (57 mg). To this material were added 1,4-dioxane (1 mL), triethylamine (0.049 mL) and diphenylphosphoryl azide (0.026 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/5). The product was suspended in a mixed solvent (n-hexane/ethyl acetate=1/1), and collected by filtration. The collected material was washed with the same solvent, and dried under reduced pressure to give the title compound (20 mg).