Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.N1C(C)=CC=CC=1C.[Br:24][C:25]1[CH:26]=[C:27]([CH2:31]O)[CH:28]=[N:29][CH:30]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[N:29][CH:28]=[C:27]([CH2:31][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCc1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (1.174 ml, 5.11 mmol) was added to 2,6-lutidine (0.743 ml, 6.38 mmol) and (5-bromopyridin-3-yl)methanol (800 mg, 4.25 mmol) stirred in CH2Cl2 (10 ml) cooled to 0° C. and the mixture was stirred at 0° C. for 1 h. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to provide 3-bromo-5-({[tertbutyl(dimethyl)silyl]oxy}methyl)pyridine: MS: cal'd 325 (MNa+), exp 325 (MNa+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=3)[N:11]([CH3:21])[C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1)C(OO)=O.[NH3:34].O1CCOCC1>C(Cl)Cl>[NH2:34][C:14]1[N:13]=[C:12]2[N:11]([CH3:21])[C:10](=[O:22])[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=3)[CH2:18][C:17]2=[CH:16][N:15]=1
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(N)c1)C2
Reactant: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(N)nc21
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of Example A1 (400 mg, 1.3 mmol) in CH2Cl2 (5 mL) was added 3-chloroperoxybenzoic acid (mCPBA) (430 mg, 2.5 mmol) in one portion. After stirring for 2 h, the reaction mixture was quenched with aq NaHCO3 and aq NaHSO3. The organic layer was separated and was washed with brine, dried Na2SO4) and concentrated in vacuo. The crude product was dissolved in DMSO (2 mL) and was treated with a solution of ammonia in dioxane (2 M, 30 ml, 60 mmol). The mixture stirred overnight at RT. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (276 mg, 77% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1 H), 6.96 (dd, J=8.4, 6.6 Hz, 1 H), 6.68 (dd, J=6.3, 2.1 Hz, 1 H), 6.52 (br s, 2 H), 6.44 (m, 1 H), 5.18 (s, 2 H), 4.48 (s, 2 H), 3.19 (s, 3 H); MS (ESI) m/z: 289.2. (M+H+).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].[NH2:21][C:22]1[C:23]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)=[CH:29][N:28]([CH:44]3[CH2:48][CH2:47][CH:46]([OH:49])[CH2:45]3)[C:24]=2[N:25]=[CH:26][N:27]=1>ClCCl>[C:9](=[O:10])([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[O:49][CH:46]1[CH2:47][CH2:48][CH:44]([N:28]2[C:24]3[N:25]=[CH:26][N:27]=[C:22]([NH2:21])[C:23]=3[C:30]([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:35][CH:36]=3)=[CH:29]2)[CH2:45]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N-Methylmorpholine (0.007 ml, 0.062 mmol) was added dropwise to solution of 4-nitrophenyl chloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 ml) with stirring under nitrogen at 0° C. After 20 minutes, the ice-water bath was removed and the mixture was allowed to warm up to ambient temperature. 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol (20 mg, 0.052 mmol) was added to the mixture and the resulting solution was stirred for 24 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium bicarbonate, and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (4-nitrophenyl) carbonate. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].[C:19](=[S:21])=[S:20].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CS(C)=O>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][S:20][C:19]([N:2]2[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:21])=[CH:26][CH:25]=1
Reactant: S=C=S
Reactant: COc1ccc(CBr)cc1
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(CSC(=S)N2Cc3[nH]c4ccccc4c3CC2C(=O)O)cc1
Yield: 79 %

Procedure:
In the same manner as described in Example 16, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.32 g), 10N NaOH (4 ml), carbon disulfide (1.4 ml), dimethylsulfoxide (20 ml) and 4-methoxybenzyl bromide (4.02 g) are reacted and treated. The product is crystallized from isopropyl ether to give the title compound (6.50 g, 79%) as colorless needles, m.p. 195°-196° C.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[N:19]([C:22]1[CH:39]=[CH:38][C:25]([CH2:26][O:27][C:28]([N:30]2[C@H:34]([C:35]([OH:37])=O)[CH2:33][S:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1)=[N+:20]=[N-:21].[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C@@H:58]([CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])[C:59]([OH:61])=[O:60])=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(O)=O>[CH:49]1[C:50]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C@@H:58]([CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:35]([C@@H:34]3[CH2:33][S:32][CH2:31][N:30]3[C:28]([O:27][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([N:19]=[N+:20]=[N-:21])=[CH:39][CH:38]=3)=[O:29])=[O:37])[C:59]([OH:61])=[O:60])=[O:56])[C:52]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]=2[CH:46]=[CH:47][CH:48]=1
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)N2CSC[C@H]2C(=O)O)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: [N-]=[N+]=Nc1ccc(COC(=O)N2CSC[C@H]2C(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (2.85 g, 10.3 mmol) was added to a solution of (R)-3-(((4-azidobenzyl)oxy)carbonyl)thiazolidine-4-carboxylic acid (Acbz-Thz-OH) (Compound SP610) (3.17 g, 10.3 mmol) in dimethylformamide (DMF) (17.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. A solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-aminohexanoic acid (Fmoc-Lys-OH) hydrochloride (4.16 g, 10.3 mmol) and diisopropylethylamine (DIPEA) (2.69 ml, 15.4 mmol) in dimethylformamide (DMF) (17 ml) was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 4 hours. Formic acid (1.9 ml) was added to the reaction solution, and the mixture was purified by reverse-phase silica gel chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((R)-3-(((4-azidobenzyl)oxy) carbonyl) thiazolidine-4-carboxamido)hexanoic acid (Fmoc-Lys(Acbz-Thz)-OH) (Compound SP611) (3.48 g, 51%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([F:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:34][C:27]1[C:28]([OH:33])=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:9]=[C:10]([CH3:11])[C:2]=1[F:1]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1F
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-3-methyl-benzoic acid (558 mg, 2.25 mmol, 1.0 eq) in DCM (30 mL) at 0° C. was added (COCl)2 (856 mg, 0.57 mL, 6.74 mmol, 3 eq) and DMF (2 drops). The reaction was stirred at 0° C. for 2 h then the solvent was removed in vacuo. The residue was taken up in THF (30 mL) and added to a suspension of 3-amino-2,4-difluorophenol (intermediate X(a)) (330 mg, 2.36 mmol, 1.05 eq) and NaHCO3 (566 mg, 6.74 mmol, 3.0 eq) in THF (30 mL) at 0° C. The reaction was stirred for 3 h at 0° C. then quenched by addition of 1 M HCl and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by chromatography (MeOH:DCM, 0:1 to 1:50) to give the title compound as a solid (360 mg, 43%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:27][C:24]=1[CH:25]=O>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:25][C:24]2[CH:27]=[C:28]([CH2:33][C:34]([F:35])([F:36])[F:37])[C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Reactant: COc1cc(OC)c(CC(F)(F)F)cc1C=O
Product: COc1cc(OC)c(CC(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 12 and Compound 85 in the same manner of Compound 13.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: COC(=O)CCNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of (R)-3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic acid (22.1 mg, 0.060 mmol) in THF (0.6 mL) and methanol (0.1 mL), aqueous 1M NaOH (0.12 mL, 0.12 mmol) is added at room temperature. After stirring for 3 hours, additional aqueous 1M NaOH (0.12 mL, 0.12 mmol) is added. The reaction mixture is allowed to stir for 30 minutes and quenched with 0.5 mL of aqueous 1M HCl and 0.5 mL of brine. The mixture is extracted twice with ethyl acetate, and the organic layer is concentrated under reduced pressure to give (R)-3-(biphenyl-4-ylmethyl)-4-(2-carboxyethylamino)-4-oxobutanoic acid (16.4 mg). HPLC retention time=1.04 minutes (condition A); MS (m+1)=356.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13-2.31 (m, 3H) 2.59-2.65 (m, 1H) 2.81-2.90 (m, 2H) 3.12-3.27 (m, 2H) 7.26 (d, 2H, J=8 Hz) 7.34 (t, 1H, J=7.4 Hz) 7.45 (t, 2H, J=7.7 Hz) 7.57 (d, 2H, J=8.1 Hz) 7.63-7.65.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]12CC(CC1)C[CH:24]2N>>[CH:5]12[CH2:4][CH:3]([CH2:23][CH2:24]1)[CH2:2][CH:1]2[NH:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CC2CCC1C2
Product: Cc1nc(NCc2ccccn2)nc(NC2CC3CCC2C3)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using bicyclo[2.2.1]hept-2-ylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.80-0.94 (m, 1H), 0.98-1.06 (m, 1H), 1.10-1.19 (m, 1H), 1.26-1.36 (m, 2H), 1.48-1.56 (m, 1H), 1.65-1.77 (m, 1H), 1.93 (s, 3H), 2.07 (s, 3H), 2.12-2.20 (m, 1H), 2.22-2.30 (m, 1H), 2.50-2.58 (m, 1H), 3.70-3.80 (m, 1H) 4.42-4.51 (m, 2H), 7.20-7.27 (m, 1H) 7.50-7.58 (m, 1H), 7.68-7.80 (m, 1H), 8.65 (d, J=4.92 Hz, 1H); MS (ESI) m/z 324.0 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[O:20]1[CH2:21][CH2:22][N:17]([C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=[C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:4]=2)[CH2:18][CH2:19]1
Reactant: N#Cc1cnc(Nc2cc(N3CCOCC3)c(Cl)cn2)cn1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cnc(Nc2cc(N3CCOCC3)c(-c3ccccc3)cn2)cn1
Temperature: 150 °C
Yield: 27.9 %

Procedure:
A mixture of 5-(5-chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile (50 mg, 0.16 mmol), phenylboronic acid (38 mg, 0.31 mmol), sodium carbonate (41 mg, 0.39 mmol) and Bedford catalyst (1 mg, 0.01 mmol) in a mixture of acetonitrile-water (4:1, 2.5 mL) was heated at 150° C. by microwave irradiation for 30 minutes. The crude reaction mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Preparative TLC, eluting with ethyl acetate-hexane (2:3) gave 5-(4-morpholino-5-phenylpyridin-2-ylamino)pyrazine-2-carbonitrile as a yellow solid (16 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7].Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1ccccc1Cl)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCc1ccccc1Cl
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
To a 50 liter flask was added diethyl o-chlorobenzylmalonate (6067 g, 21.31 mol), glacial acetic acid (1090 mL), and concentrated hydrochloric acid (16,000 mL). The reaction was then heated at reflux for 21 hours and 13 minutes. Additional concentrated hydrochloric acid (1840 mL, 5520 mL total) was added at 3.5, 13.5, and 17 hours into the reflux. The reaction was cooled to 0°±2° C. and the resulting solid was collected by suction filtration and washed with water (4L). The solid was suspended in water (8L) and the slurry was stirred for five minutes. The solid was collected by suction filtration and washed with water (20L). The filtrate was pH 2 and tested positive for chlorine. The solid was then washed seven times in the following manner; the solid was suspended in water (8L) and stirred for approximately ten minutes. The solid was collected by suction filtration and washed with water (4L). The filtrate was tested for chloride ion and the pH was recorded. The final filtrate was pH 4.5-5 and tested negative to the presence of chloride ion. A total of 100 liters of water was used to wash the solid. The solid was dried under vacuum at 35°±3° C. for 70 hours to give crude β-2-chlorophenylpropionic acid (3653 g, 93.4%) as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([C:34]2[CH:35]=[CH:36]C3C=CS[C:38]=3[CH:42]=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(O)(=O)C1C=C[N:47]=CC=1>>[CH:1]([NH:4][C:5]([C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32](=[O:33])[C:34]2[CH:35]=[CH:36][N:47]=[CH:38][CH:42]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: O=C(O)c1ccncc1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccncc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 44.2 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using isonicotinic acid. After preparative HPLC purification, the TFA salt was free-based using an SCX-ion exchange column to obtain (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)isonicotinamide as a tan solid (44.2% yield). MS m/z=534.2 [M+H], calc 533.67 for C29H39N7O3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+](CC)CC)[CH3:21]>>[F:15][B-:16]([F:19])([F:18])[F:17].[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[NH:8])[O:7][CH2:20][CH3:21])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:3]=1
Reactant: CC[O+](CC)CC
Reactant: CCCOc1cc(C)ccc1C(N)=O
Agent: F[B-](F)(F)F
Product: CCCOc1cc(C)ccc1C(=N)OCC

Procedure:
reaction of 4-methyl-2-propoxybenzamide (11.96 g) with triethyloxonium tetrafluoroborate yielded crude ethyl 4-methyl-2-propoxybenzimidate tetrafluoroborate which on reaction with a saturated solution of ethanolic ammonia and treatment with hydrochloric acid yielded 4-methyl-2-propoxybenzamidine hydrochloride, (8.74 g), m.p. 228-30° C.;
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH2:11]Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:11][CH:10]=[CH:9][C:8]3[CH:13]=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: CS(=O)(=O)c1ccc(C=CCCl)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 21 %

Procedure:
Prepared from 4-methylsulphonyl-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 21% of theory, Melting point: 157°-161° C. (ether).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.N1[C:27]2[C:18](=[CH:19][CH:20]=[C:21]3[C:26]=2N=CC=C3)[CH:17]=CC=1.C(=O)([O-])[O-:29].[Cs+].[Cs+]>C(O)C1C=CC=CC=1.C(Cl)Cl.[Cu]I>[CH2:17]([O:29][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1)[C:18]1[CH:27]=[CH:26][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc(N2CCNCC2)nc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: c1ccc(COc2ccc(N3CCNCC3)nc2)cc1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A vigorously stirred suspension of 1-(5-bromopyridin-2-yl)piperazine (CAS number 73406-97-0, 116 g, 479 mmol), 1,10-phenanthroline (17.3 g, 96 mmol), Cesium carbonate (312 g, 960 mmol) and Copper (I) iodide (91 g, 480 mmol) in benzyl alcohol (960 mL) was stirred at 120° C. under an inert atmosphere for 24 hours, adding further aliquots of copper (I) iodide (5×91 g) every hour. Cooled to 40° C. and diluted with DCM (1L), stirring at room temperature for 30 minutes. Filtered through celite, washing well with DCM (500 mL). The fractions were washed with NaOH (2M, 300 mL), combined and extracted with HCl (2M, 5×1L). The combined acidic extracts were washed with DCM (500 mL), cooled to 0° C. and extracted into DCM (1L), basifying slowly with NaOH (˜46 wt %) to pH10. The aqueous layer was further extracted with DCM (2×500 mL) and the volatiles removed in vacuo, to give 1-[5-(benzyloxy)pyridin-2-yl]piperazine as a black liquor (104 g, 278 mmol @ 72 wt %, 58%).
Reaction SMILES: [CH2:1]([C@@:4]1([O:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])CO)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:32][NH:33][S:34]([CH:37]1[CH2:39][CH2:38]1)(=[O:36])=[O:35].[C:40](C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([O:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:32][N:33]([CH3:40])[S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CNS(=O)(=O)C1CC1
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Reactant: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methoxypiperidin-2-one (124 mg, 0.268 mmol; Example 203, Step D) in toluene (1.3 mL) was added N-methylcyclopropanesulfonamide (109 mg, 0.804 mmol). The mixture was evacuated and backfilled with argon (5×). Cyanomethylenetributylphosphorane (0.211 mL, 0.804 mmol) was added. The mixture was evacuated and backfilled with argon (5×). The mixture was heated in a 70° C. oil bath for 12 hours then cooled to room temperature and stirred for 2 days at room temperature. The mixture was loaded onto silica gel and the product was eluted with 20-60% ethyl acetate/hexanes. The residue was one more time purified by flash chromatography on silica gel (12 g column, eluent: 10 to 60% ethylacetate/hexanes) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][C:14]=1[F:27].[CH3:28][O:29][CH:30](OC)[CH2:31]OC>>[F:27][C:14]1[CH:15]=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][CH2:31][CH2:30][O:29][CH3:28])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: COCC(OC)OC
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)cc3F)c2c1
Product: COCCNc1ccc2ncnc(Nc3ccc(OCc4ccccn4)cc3F)c2c1
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 43, 6-amino-4-[2-fluoro-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-[2-fluoro-4-(2-pyridylmethoxy)anilino]-6-(2-methoxyethylamino)quinazoline in 52% yield;