Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([NH:16][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CCCCCCN
Product: CCCCCCNc1cc(C)cc(C)c1
Yield: 91.1 %

Procedure:
Using the general procedure, 5-bromo-m-xylene (136 μL, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent afforded the desired product as a colorless oil (187 mg, 91% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH3:15])[CH2:11][C:12](O)=[O:13])=[CH:5][CH:4]=1.O.[NH2:18][NH2:19]>C(O)(C)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]([CH3:15])[CH2:11][C:12](=[O:13])[NH:18][N:19]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CSc1ccc(C(=O)C(C)CC(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CSc1ccc(C2=NNC(=O)CC2C)cc1

Procedure:
2.3 g (0.01 mole) of 4-(4-methylthio-phenyl)-4-oxo-3-methyl-butyric acid and 1 ml of hydrazine hydrate are heated under reflux in 20 ml of isopropanol for 2 hour. After the mixture has been cooled, the product is filtered off with suction and dried.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11](OCC)=[O:12])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]1[CH:31]([C:32]([OH:34])=O)[CH2:30][C:28](=[O:29])[CH2:27]1.O[N:36]1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C@@H:31]1([C:32]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:36])=[O:12])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[S:4][C@H:3]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:34])[CH2:26][CH2:27][C:28](=[O:29])[CH2:30]1
Reactant: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2ccccc21
Reactant: O=C1CCC(C(=O)O)C1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)[C@@H]2CCC(=O)C2)[C@H](c2ccccc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of 10 ml of dry dimethylformamide of 511 mg of ethyl 3(R)-amino-4-oxo-2(S)-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 200 mg of 3-cyclopentanone-1(R)-carboxylic acid which is prepared according to the known procedure and 322 mg of 1-hydroxybenzotriazole is added 322 mg of dicyclohexylcarbodiimide. After allowing to stand overnight, the precipitated dicyclohexylurea is filtered off. The dimethylformamide was distilled off under reduced pressure, and to the residue is added chloroform. After washing with an aqueous solution of sodium chloride and drying over magnesium sulfate, the solvent is distilled off. The residue is subjected to column chromatography on silica gel and crystallized from benzene to give 540 ml of 3(R)-[3-cyclopentanone-1(R)-carboxamido]-4-oxo-2(S)-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p.=135°- 150° C.
Reaction SMILES: [NH2:1][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH2:3]1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH3:9][C:4]1([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]([N:1]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3]1
Reactant: BrCCOCCBr
Reactant: CCOC(=O)C1(N)CCCC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N2CCOCC2)CCCC(C)(C)C1
Temperature: 95 °C

Procedure:
To a solution of EXAMPLE 145C (3.5 g) in N,N-dimethylformamide (30 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (5.8 g) and K2CO3 (6.5 g). The reaction mixture was heated to 95° C. for 18 hours. The mixture was cooled to room temperature, diluted with water, and extracted with methylene chloride (3×50 mL). The combined organic layers were washed with saturated NaCl solution (1×25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 4:1 petroleum ether/ethyl acetate solution, to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:43]([C:40]3[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=3)(=[O:45])=[O:44])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NS(=O)(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using the following starting materials: {4′-amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester and 4-chlorobenzenesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(OCC)(=O)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[S:37]([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)([O-:40])(=[O:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 37.5 °C
Reaction time: 2 h
Yield: 223.7 %

Procedure:
5.0 g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml ethyl acetate and 2.55 g of 3-aminophenyl acetylene was charged at 25-30° C. 0.9 g of p-toluyl sulphonic acid was added. The reaction mass was heated and stirred at 35-40° C. for 2 hours. The solid obtained was filtered and washed with ethyl acetate. The product was dried at 38-40° C. to obtain 6.6 g of erlotinib tosylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:9])=[CH:3][C:2]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Nc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(F)c(-c2cccnc2)c1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
A mixture of 3-bromo-4-fluorophenylamine (7.92 g, 41.7 mmol), diethyl(3-pyridyl)borane (6.74 g, 45.9 mmol), tetrakis(triphenylphosphine)palladium(0) (0.96 g, 0.83 mmol) and potassium carbonate (17.26 g, 125 mmol) in 1,2-dimethoxyethane (30 ml) and water (15 ml) was heated at 80° C. for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (500 ml) and water (500 ml). The organics were washed with brine (400 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, 0-20% EtOAc/CH2Cl2) gave 4-fluoro-3-(pyridin-3-yl)phenylamine (3.64 g, 46%) as a colourless oil that solidified on standing to afford a white solid: 1H NMR (360 MHz, CDCl3) δ 3.65 (2H, s), 6.65-6.72 (2H, m), 6.99 (1H, dd, J 9, 9 Hz), 7.33-7.37 (1H, m), 7.84-7.86 (1H, m), 8.58 (1H, d, J 4 Hz), 8.76 (1H, m).
Reaction SMILES: C(OCC)(=O)C.[CH2:7]([N:9]([CH2:12][CH3:13])[CH:10]=[O:11])[CH3:8].[C:14]1([C@@H:20]2[CH2:22][C@@H:21]2[C:23](=[O:26])[CH2:24]C)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC>[CH2:7]([N:9]([CH2:12][CH3:13])[CH:10]=[O:11])[CH3:8].[C:14]1([C@@H:20]2[CH2:22][C@@H:21]2[C:23](=[O:26])[CH3:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCC(=O)[C@H]1C[C@H]1c1ccccc1
Agent: CCN(C=O)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)[C@H]1C[C@H]1c1ccccc1
Yield: 95 %

Procedure:
Compounds 20a and 20b (each, 3.73 mmol) obtained in Reference Example 14 were individually dissolved in 20 ml of anhydrous tetrahydrofuran. To each of the resultant solutions was added a solution of 0.93M diisobutylaluminumhydride in hexane (7.46 mmol) in a stream of argon gas at -78° C. Each of the resultant mixtures was stirred at -78° C. for 1 hour to effect a reaction. 1N hydrochloric acid was added to each of the reaction mixtures to thereby terminate the reaction. The resultant mixture was subjected to distillation under reduced pressure to thereby remove the solvent and obtain a residue. Water was added to each of the obtained residues, and ethyl acetate was further added for extraction to thereby obtain an organic layer. Each of the organic layers was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain a residue. Each of the obtained residues was purified by silica gel column chromatography (the composition of the developing solvent for the residue obtained from compound 20a was; ethyl acetate:hexane =1:1, and the composition of the developing solvent for the residue obtained from compound 20b was; ethyl acetate:hexane=1:2). As a result, compound 21a was obtained from compound 20a (yield: 95%), and compound 21b was obtained from compound 20b (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:30]2[CH2:31][CH2:32][C:27]([OH:26])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:29]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc2c1C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: OC1(c2ccccc2)CCNCC1
Product: COc1cccc2c1C(=O)N(C)C2C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 115.9 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(4-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.95 g) was coupled to 4-hydroxy-4-phenylpiperidine (0.44 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.838 g); mp 163°-185° C.; MS: m/z=539(M+1); NMR(CD3SOCD3): 1.78 (m,2), 2.10 (m,1), 2.98-3.22 (two peaks,3), 3.77 (s,3), 4.77 (m,1), 5.45 (m,1) 6.69-7.58 (m,11). Analysis for C30H32Cl2N3O2.1.0.HCl,1.0H2O: Calculated: C, 60.66; H, 5.94, N, 4.71; Found: C, 60.67; H, 5.94; N, 4.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][CH:8]=[C:9]([S:10](Cl)(=[O:12])=[O:11])[C:5]=2[CH:4]=1.[NH3:16]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][CH:8]=[C:9]([S:10]([NH2:16])(=[O:12])=[O:11])[C:5]=2[CH:4]=1
Reactant: N
Reactant: COc1ccc2scc(S(=O)(=O)Cl)c2c1
Solvent: C1CCOC1
Product: COc1ccc2scc(S(N)(=O)=O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-methoxy-benzo[b]thiophene-3-sulfonyl chloride(0.80 g, 3.08 mmol) in THF (20 mL) was added ammonia gas until saturation at ca. 10° C., then the flask was stoppered, and the reaction mixture was stirred at rt for 4 h. The reaction mixture was then quenched with water; the organic solvent was slowly evaporated under vacuum. The precipitate formed was filtered off, washed with water and dried over P2O5 under high vacuum to obtain the desired compound (0.64 g) as a yellowish solid. MS (ISN): m/e 239.4 (M−H)−
Reaction SMILES: CS(O[CH2:6][CH2:7][C@:8]1([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=2)[O:12][CH2:11][N:10]([C:13](=[O:28])[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[CH2:9]1)(=O)=O.[NH:37]1[CH2:42][CH2:41][C:40]2([C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44][C@@H:43]2[O:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:39][CH2:38]1>>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([C:24]([F:25])([F:27])[F:26])[CH:17]=1)[C:13]([N:10]1[CH2:9][C@@:8]([CH2:7][CH2:6][N:37]2[CH2:42][CH2:41][C:40]3([C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][C@@H:43]3[O:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:39][CH2:38]2)([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=2)[O:12][CH2:11]1)=[O:28]
Reactant: CCOC(=O)CO[C@H]1Cc2ccccc2C12CCNCC2
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(F)c(Br)c2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CO1
Product: CCOC(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)c(Br)c3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Yield: 67.2 %

Procedure:
The compound (470 mg, 0.77 mmol) obtained in Example 91i and the compound (335.4 mg, 1.16 mmol) obtained in Example 1h were used to give the title compound (415 mg; yield, 67%) as a white solid according to the method described in Example 1i.
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]5[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=5)[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].O>C(Cl)Cl>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]5[N:28]=[CH:27][C:26]([NH:29][C:39](=[O:41])[CH3:40])=[CH:25][N:24]=5)[CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(=O)Cl
Reactant: Nc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-{4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidin-5-ylamine (Example 107) (0.32 mmol) was dissolved in DCM and triethylamine (2 eq.) was added. The reaction was cooled to 0° C., acetylchloride (1 eq.) was added dropwise and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography of the resulting oil (DCM/MeOH) provided the expected product. 1H NMR (CDCl3): δ 8.84 (1H, s), 8.36 (2H, s), 7.55 (2H, m), 7.19 (1H, s), 7.11 (2H, m), 6.94 (1H, s), 5.16 (2H, s), 4.77 (2H, m), 3.25 (1H, m), 3.01 (2H, m), 2.16 (2H, m), 2.15 (3H, s), 1.75 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].N1(C(C2C=CC(Br)=CC=2[F:42])=O)CCC1.COC(C1C=C(O)C=C2OC(C)(C)CC=12)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])=[C:19]([F:42])[CH:18]=2)[CH:8]=[C:7]2[O:11][C:10]([CH3:9])([CH3:12])[CH2:13][C:6]=12)=[O:4]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)cc2c1CC(C)(C)O2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)cc2c1CC(C)(C)O2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from azetidin-1-yl-(4-bromo-2-fluoro-phenyl)-methanone and 6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197e). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.07 Hz, 1 H) 7.37 (d, J=1.77 Hz, 1 H) 7.29 (dd, J=9.35, 1.52 Hz, 1 H) 7.15 (d, J=2.27 Hz, 1 H) 6.62 (d, J=2.27 Hz, 1 H) 4.16-4.25 (m, 2 H) 4.07-4.16 (m, 2 H) 3.87-3.88 (m, 3 H) 3.33 (s, 2 H) 2.29-2.39 (m, 2 H) 1.51 (s, 6 H); LCMS for C22H22FNO5 m/z 441.30 (M+H)+.
Reaction SMILES: [C:1]([CH:5]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:24]3=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]3[N:22]=[C:21]2[CH2:31][CH3:32])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:3][CH3:4])=[O:2].[CH2:33](Br)[CH:34]([CH3:36])[CH3:35]>>[C:1]([CH:5]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:24]3=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]3[N:22]=[C:21]2[CH2:31][CH3:32])=[CH:15][CH:14]=1)[CH2:33][CH:34]([CH3:36])[CH3:35])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([O:3][CH3:4])=[O:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Reactant: CC(C)CBr
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(CC(C)C)C(C(=O)OC)c2ccccc2)cc1

Procedure:
Using the general procedure for the alkylation of secondary amines described in Step A of Example 29, 3-[4-(N-(1-carbomethoxy-1-phenylmethylamino)phenylmethyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (Step A, Example 28) was alkylated with iso-butyl bromide. Standard workup and purification by flash chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:16][CH:17]=1)[CH3:10]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1ccc(-c2ccnc(Cl)n2)cc1

Procedure:
2,4 dichloropyrimidine was coupled with 3-ethoxyphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 235.
Reaction SMILES: C([N:8]1[CH:13]([CH3:14])[CH2:12][CH:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)C1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1COCC1>[CH3:14][CH:13]1[N:8]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH2:12]1
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)C1=CCC(C)N(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC(C(=O)OC)=CCC1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of methyl 1-benzyl-6-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate (2.05 g, 8.36 mmol) in THF (15 ml) were added at 0–5° C. allyl chloroformate (1.1 ml, 10.4 mmol). The mixture was immediately raised to room temperature and stirred for 18 hours. After cooled to 0–5° C. a saturated aqueous sodium hydrogen carbonate and ethy acetate were added thereto and the mixture was separated with a separating funnel. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel (55 g) chromatography (hexane/ethyl acetate=6/1→4/1) to give 1-allyl 3-methyl 6-methyl-5,6-dihydro-1,3(2 H)-pyridinedicarboxylate (1.42 g, 71%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([C:12]#[N:13])(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N12CCCN=C1CCCCC2>ClCCl.O1CCCC1.[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:1][C:2]1[N:3]=[N:4][C:5]([C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: Cc1cccnn1
Reactant: C[Si](C)(C)C#N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(C#N)nn1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a stirring solution of 3-methylpyridazine (11 g, 118 mmol) in dichloromethane (200 mL) was added AlCl3 (0.05 g) followed by trimethylsilylcyanide (21 g, 211 mmol). After 20 min, a solution of p-toluenesulfonyl chloride (38 g, 201 mmol) in dichloromethane (50 mL) was added via addition funnel and the solution continued to stir overnight. The next morning, the solvent was removed in vacuo and the residue was suspended in ethanol with stirring for 15 min and then filtered to give a white solid. The solid was dissolved in tetrahydrofuran (200 mL) and to this stirring solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (16 mL, 105 mmol). After 1 h, the solvent was removed in vacuo and the residue was partitioned between hexanes and saturated aqueous NH4Cl. The phases were separated and the aqueous phase was basified with solid Na2CO3, then extracted three times with ethyl acetate. The combined ethyl acetate phases were dried (MgSO4), filtered and concentrated in vacuo to give 9 g (64%) of white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30](O)=[O:31])=O)[CH2:13][CH2:12]1.C(OC(=O)C)(=O)C.[CH3:40][NH2:41].CO>O1CCCC1>[CH3:40][N:41]1[C:30](=[O:31])[C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=2[N:23]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:12][CH2:13]1
Reactant: CN
Reactant: O=C(CCCCN1CCN(c2ccc3ccccc3n2)CC1)NC1=C(C(=O)O)CCCC1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CCCC2
Temperature: 25 °C
Yield: 89.3 %

Procedure:
In 30 ml of tetrahydrofuran, 10.0 g of 2-[5-(4-quinolin-2-ylpiperazin-1-yl)-pentanoylamino]cyclohex-1-enecarboxylic acid as synthesized in above Step 7-1-E was suspended, and to the suspension, 7.0 g of 3 equivalent of acetic anhydride was added, followed by an hour's heating under reflux. The solution was cooled with ice, and while continuing the cooling, 35.6 ml of excessive 40% methylamine-methanol solution was gradually added. After about 10 minutes' refluxing under stirring, the temperature was cooled to room temperature and the solution was concentrated under reduced pressure. After addition of 80 ml of distilled water and 30 minutes' stirring, precipitated crystals were recovered by filtration and dried to provide 8.83 g (89.3%) of 3-methyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one.