Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:35])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)#[N:2].Cl.[CH3:42][NH2:43]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:13])[NH:43][CH3:42])=[CH:15][CH:16]=1)[CH:17]1[CH2:18][CH2:19][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:35])[CH2:21][CH2:22]1)#[N:2]
Reactant: CN
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CNC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Yield: 71.2 %

Procedure:
Using general procedure E, 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 131) (30 mg, 0.056 mmol) and methylamine hydrochloride (19 mg, 0.28 mmol) afforded COMPOUND 132 as a white solid (22 mg, 72%). 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.3 Hz), 1.15-1.26 (m, 1H), 1.52-1.75 (m, 4H), 2.15-2.37 (m, 2H), 2.31 (s, 6H), 2.59 (t, 1H, J=11.1 Hz), 2.76-2.88 (m, 3H), 2.96 (d, 3H, J=4.2 Hz), 3.20-3.33 (m, 1H), 3.67-3.74 (m, 1H), 3.85-3.89 (m, 1H), 3.89 (s, 2H), 5.91 (br s, 1H), 6.52 (d, 2H, J=8.4 Hz), 6.96 (d, 2H, J=7.2 Hz), 7.04-7.09 (m, 1H), 7.41-7.46 (m, 3H), 7.54-7.57 (m, 3H), 8.25 (br s, 1H). 13C NMR (CDCl3) δ 13.85, 19.54, 27.07, 29.47, 30.73, 31.40, 40.13, 43.97, 48.36, 52.39, 56.37, 60.80, 112.55, 113.05, 119.20, 123.36, 127.70, 128.80, 128.86, 129.76, 130.13, 131.07, 134.52, 139.01, 141.73, 150.81, 168.13, 170.24. ES-MS m/z 552 (M+H). Anal. Calcd. for C34H41N5O2.0.9H2O: C, 71.90; H, 7.60; N, 12.33. Found. C, 71.72; H, 7.71; N, 12.72.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH:11]1[N:15]=[CH:14][N:13]2[CH2:16][CH2:17][C:18](=[O:19])[C:12]=12>>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([C:18]3([OH:19])[C:12]4[N:13]([CH:14]=[N:15][CH:11]=4)[CH2:16][CH2:17]3)=[CH:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2sccc2c1
Reactant: O=C1CCn2cncc21
Product: OC1(c2cc3cc(F)ccc3s2)CCn2cncc21
Yield: 34.6 %

Procedure:
The reaction and purification in the same manner as in Example 1 using 5-fluorobenzo[b]thiophene (0.30 g) and 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (0.18 g) afforded the title compound (0.14 g) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][C:9]=1[CH3:17])(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([CH3:17])[CH:10]=1)#[N:16]
Reactant: Cc1cc(CC#N)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC#N)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
The compound (1.16 g) obtained in Example 520 was dissolved in methylene chloride (15 ml); to the solution, trifluoroacetic acid (4 ml) was added and the mixture was stirred at room temperature for 1 h. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with methylene chloride. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 480.5 mg of the titled compound (yield, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol) (Aldrich), followed by the addition of acetyl chloride (20 mg, 0.24 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give rac-3-(1-acetyl-piperidin-3-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 58 mg, 66%). Further purification by precipitation from dichloromethane-hexanes gave the product as a white solid. (Yield 45 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=1)[C:5]#[N:6].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.Cl>C(O)C>[Cl:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([NH:1][C:2]3[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][CH2:12][N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH:9]=3)[C:5]#[N:6])=[CH:21][CH:22]=[N:23]2)=[CH:28][CH:27]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: N#Cc1cc(N)cc(NCCN2CCCCC2)c1
Agent: Cl
Solvent: CCO
Product: N#Cc1cc(NCCN2CCCCC2)cc(Nc2ccnc3cc(Cl)ccc23)c1
Yield: 15.4 %

Procedure:
3-amino-5-{[2-(piperidin-1-yl)ethyl]amino}benzonitrile (200 mg, 0.82 mmol) and 4,7-dichloroquinoline (162 mg, 1 eq) were refluxed in 15 mL of ethanol and 0.82 mL of HCl 1M for 24 h. The reaction mixture was then evaporated and the residue and was purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH//95/5/1) to yield expected compound as a yellow powder (51 mg, 15% yield). m/z (ESI) 406.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Temperature: 25 °C

Procedure:
4-carboxyphthalic anhydride (benzene tricarboxylic acid anhydride) (1.0 g, 0.0052 mol), glycine (0.3907 g, 0.0052 mol) and 50–60 mls of glacial acetic acid were added to a 100 ml round-bottom flask equipped with a reflux condenser, heating mantle and stir plate. The system was placed under a N2 atmosphere and heated to a gentle reflux. The progress of the reaction was monitored by TLC. After 7 hours the clear colourless solution was cooled to room temperature. The resulting white precipitate was filtered through a Buchner funnel and washed three times with 10 mls of distilled water. This crude material was recrystallized in EtOH/H2O to afford the desired product as a powdery white solid. The filtrate was evaporated under vacuum using a rotary evaporator. The crude material was recrystallized from EtOH/H2O to yield a second batch of white powdery product. Individual batches were dried in air for 24 hours and then in vacuo for 48–72 hours to afford 100 in a combined yield of 1.02 g (78%): mp=262–265° C.; Rf 0.70 (A): Rf 0.47 (B): Rf 0.20 (D): 1H NMR (DMSO-d6) δ 4.33 (s, 2H), 8.02 (d, J=7.8 Hz, 1H), 8.24 (bs, 1H), 8.36 (d, J=7.8 Hz, 1H); MS m/z (rel intensity) 249 (13), 248 (100), 204 (36); IR (cm−1): 2750–3300 (OH), 3052 (C═CH), 2671 (C—H), 1776 (C═O), 1731 (C═O), 1705 (C═O), 1620 (C═C), 1420 (C═C), 1300 (C—O), 1122 (C—O), 746 (C═CH).
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[N:19][C:20]=1[CH:21](OC)[O:22]C)[N:17]([C:26]([NH:28][C:29]1[CH:34]=[C:33]([NH:35][CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])[C:32]([C:41]#[N:42])=[CH:31][N:30]=1)=[O:27])[CH2:16][CH2:15][CH2:14]2)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:41]([C:32]1[C:33]([NH:35][CH2:36][C:37]([OH:40])([CH3:38])[CH3:39])=[CH:34][C:29]([NH:28][C:26]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([CH2:10][OH:9])=[C:20]([CH:21]=[O:22])[N:19]=3)[CH2:14][CH2:15][CH2:16]2)=[O:27])=[N:30][CH:31]=1)#[N:42]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(NCC(C)(C)O)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CNc1cc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)ncc1C#N
Reaction time: 4.5 h

Procedure:
Concentrated hydrochloric acid (0.17 ml) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 78C, 30 mg, 0.051 mmol) in THF (1 ml) and water (0.5 ml) at room temperature. After stirring for 1 h at room temperature additional concentrated hydrochloric acid (0.17 ml) was added and stirring continued for a further 4.5 h. Saturated aqueous NaHCO3 was then added, the mixture extracted with DCM (2×), the organic layers dried over Na2SO4 and evaporated. The residue was purified by reversed phase preparative chromatography (RP 2) to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[H][H]>CO.[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Br)ccc1Cl

Procedure:
90 g of 5-bromo-2-chloronitrobenzene were hydrogenated in 500 ml of methanol at room temperature and under normal pressure with Raney-Nickel as catalyst and hydrogen. Colorless crystals, melting point: 47° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccccc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-(4-phenylmercapto-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)COc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
N-Ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenoxy)acetamide (0.177 g, 0.586 mmol) was dissolved in acetonitrile (10 ml), methyl 2-(bromomethyl)benzoate (0.147 g, 0.642 mmol) and dipotassium carbonate (0.161 g, 1.167 mmol) were added. The solution was stirred for 2 hours at 60° C. EtOAc (20 ml) was added and the organic phase was washed with two portions of brine (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.242 g of methyl 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenoxy)methyl]benzoate (yield 91.9%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH3:16].[CH:17]([Mg]Br)([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH3:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[CH:17]([CH3:19])[CH3:18]
Reactant: COc1cc2c(cc1Br)C(=O)CCC2(C)C
Reactant: CC(C)[Mg]Br
Product: COc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 68 %

Procedure:
Following General Procedure A, 7-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 92, 1.0 g, 3.5 mmol) was reacted with i-PrMgBr to afford 0.74 g (68%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:7]=[C:8](Br)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH3:3])[CH3:2].[CH2:23]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CCOCC.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.[Cu]I>[CH2:23]([C:28]1[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([O:5][Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:1]([CH3:3])[CH3:2])[CH:7]=2)=[CH:32][CH:33]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C#Cc1ccc(CCCCC)cc1
Reactant: CC(C)[Si](Oc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C#Cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc3ccccc23)cc1
Yield: 33.1 %

Procedure:
A solution of 3-triisopropylsilyoxy-1-bromonaphthalene (2.32 g, 6.1 mmol), (4-pentylphenyl)acetylene (1.58 g, 9.2 mmol), Pd(PPh3)2Cl2 (129 mg, 3 mol %), PPh3 (240 mg, 15 mol %) and CuI (88 mg, 7.5 mol %) in Et3N (20 mL) under N2 was heated at reflux for 4 h. The resulting mixture was cooled, diluted with Et2O, filtered and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexanes as eluent. The solvent was removed under reduced pressure to give the title compound (0.95 g, 33%) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].CN(C=O)C.Cl[C:12]1[C:13]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:23])=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>O>[CH2:3]([S:5][C:12]1[C:13]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][N:26]=2)=[O:23])=[N:14][CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1)[CH3:4]
Reactant: CCS
Reactant: O=C(Nc1ccc(C(F)(F)F)cn1)c1ncc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(C(F)(F)F)cnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107.4 %

Procedure:
0.37 g of 60% sodium hydride (oil-based) was added to a mixture of 0.34 g of ethyl mercaptan and 3 mL of DMF under ice cooling, and the mixture was stirred at room temperature for 10 minutes. 1.35 g of 3-chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Water was poured to the reaction mixture, and the precipitated solid was taken by filtration and dried under reduced pressure to obtain 1.55 g of 3-ethylsulfanyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:12]N1C(=O)CCC1=O.O>O1CCCC1>[Br:12][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(Br)[nH]c1C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1.53 g) in tetrahydrofuran (20 mL) was added N-bromosuccinimide (1.78 g) at −78° C., and the mixture was stirred at the same temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at not more than 5° C. The residue washed with hexane to give the title compound as a colorless solid (yield 2.26 g, 97%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][C:29]([NH2:31])=[O:30].O>CN(C=O)C>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:28][C:29]([NH2:31])=[O:30])[N:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:19]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Cn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and iodoacetamide (46 mg, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)− m/z calcd 319.1, found 319.2.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][CH2:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:28](=[O:27])[CH2:29][CH2:30][OH:31])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)CCO
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(CCO)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (20 mg, 20%), MS (ISP) m/z=399.3 [(M+H)+], mp 148° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-hydroxy-propionic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][N:16]=[N+:17]=[N-:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:22]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:22])[CH:10]([CH2:15][N:16]=[N+:17]=[N-:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(CN=[N+]=[N-])C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
To a stirred solution of 3-azidomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2 mmol, 0.512 g; Example 100) in DMF (5 mL) at 0° C. was added NaH (0.1 g, 60% dispersion in mineral oil) and continued stirring at 0° C. for 20 min. To this was Iodomethane (0.5 mL) and stirred at room temperature for 20 min. The volatiles were removed under reduced pressure, residue was dissolved in ethyl acetate (10 mL), washed with water, separated the organic layer, dried and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to get 3-azidomethyl-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.41 g, 76% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[S:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([S:43][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:45]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Sc2ncnc3cc(OCCOC)c(OC)cc23)c1
Yield: 29 %

Procedure:
Using the procedure described in Example 159B, ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate described in Example 166A (0.138 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureido)-1H-pyrazol-1-yl]acetate as solid (0.071 g, 29%). 1H NMR (300 MHz, DMSO-d6) δ 8.98 (br, 1H), 8.74 (s, 1H), 8.60 (s, 1H), 7.83 (s, 1H), 7.34-7.52 (m, 4H), 7.26 (d, 1H), 6.12 (s, 1H), 4.85 (s, 2H), 4.33 (m, 2H), 4.15 (q, 2H), 4.00 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.20 (s and t, 12H); LC-MS (ESI) m/z 609 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([OH:36])=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])[C:24](=[O:26])[N:25]=2)=[CH:16][CH:15]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:21][C:22]([O:36][C:9]([O:11][CH3:12])=[O:10])=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])[C:24](=[O:26])[N:25]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(-c2c(O)sc(-c3ccc(F)cc3)nc2=O)c(C)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Oc1sc(-c2ccc(F)cc2)nc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
1.0 g (10 mmol) of triethylamine and then 0.94 g (10 mmol) of methyl chloroformate in 10 ml of ethyl acetate are added dropwise at 0° C. to 3.4 g (10 mmol) of 2-(4-fluorophenyl)-6-hydroxy-5-(2,4,6-trimethyl-phenyl)-1,3-thiazin-4-one in 50 ml of ethyl acetate. The mixture is stirred for 8 hours at 20° C. and filtered, the organic phase is washed using half-concentrated sodium chloride elusion and dried over sodium sulphate, and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (35 to 70 μm) using toluene/acetone (20:1 parts by volume). 3.1 g of 2-(4-fluorophenyl)-6-methoxycarbonyloxy-5-(2,4,6-trimethylphenyl)-1,3-thiazin-4-one are obtained (yield: 78% of theory). M.p.=129° to 131° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][N:10]([CH2:15][C:14]1[CH:13]=[C:12]([F:11])[CH:19]=[C:18]([F:20])[CH:17]=1)[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(F)cc(CN(Cc2cc(F)cc(F)c2)c2ccc3[nH]cnc3c2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 3,5-difluorobenzylbromide (455 mg; 0.285 ml; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.065 g (16.7%); MS m/z: 386.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.75 (s, 4H); 6.67-6.70 (m, 2H); 6.97-6.99 (m, 4H); 7.07 (tt, 2H, 4J=2.3 Hz, 3JH,F=9.3 Hz); 7.36-7.37 (m, 1H); 7.94 (s, 1H); 11.96 (br s, 1H); HPLC (METHOD [A]): rt 16.26 min (100%)