Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4](I)[C:3]=1[F:13].C(O)CCC.C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])[C:3]=1[F:13]
Reactant: OB(O)c1ccccc1F
Reactant: Fc1c(I)nc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccccc1-c1nc2ccccc2c(Cl)c1F
Temperature: 50 °C
Yield: 64.5 %

Procedure:
To a solution of 4-chloro-3-fluoro-2-iodo-quinoline (from step D, 0.3 g, 0.9 mmol) in toluene (5 mL) was added n-butanol (2 mL), water (3 mL) and cesium carbonate (1.14 g, 3.5 mmol). The resulting mixture was degassed for 5 min. and tetrakis(triphenyl-phosphine)palladium(0) (5 mg, 5 mol %) and 2-fluorophenyl boronic acid (0.286 g, 2 mmol) were added. The reaction mixture was heated to 50° C. for 24 h., after which it was extracted with ethyl acetate. The organic layer was dried and concentrated in a rotary evaporator. The residue was purified by silica gel column chromatography using ethyl acetate/hexane gradient to yield the title compound (0.160 g, 48%). MS (ES) 336.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>O.C(O)(=O)C>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Reaction time: 2.5 h
Yield: 91 %

Procedure:
305 ml of a 1M solution of (NH4)2Ce(NO3)6 in H2O are added slowly at 10°-15° C. to 20 g (0.106 mol) of 2-butyl-4-chloro-5-hydroxymethylimidazole in 350 ml of glacial acetic acid. After 2.5 h at RT, the pH is adjusted to 4 with 2N KOH (20° C. during addition of the base). After extraction 4x with 500 ml of CH2Cl2 each time the combined organic extracts are washed 3x with 300 ml of saturated aqueous NaHCO3 solution each time, dried with Na2SO4 and concentrated, resulting in the title compound as a colorless solid (18 g). Melting point was 90° C.
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[CH:11]=[C:10]([C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)[C:9](OC)=[C:8]([C:20]#[N:21])[C:7]2=[O:22])[CH3:5])[CH2:3][CH2:2]1.O.[NH2:24][NH2:25]>C(O)C>[NH2:21][C:20]1[C:8]2[C:7](=[O:22])[N:6]([CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])[CH:11]=[C:10]([C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)[C:9]=2[NH:25][N:24]=1
Reactant: COc1c(-c2ccn(C)n2)cn(C(C)C2CC2)c(=O)c1C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C1CC1)n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A mixture of 1-(1-cyclopropylethyl)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step C of Example 163 (22 mg), hydrazine monohydrate (18 mg) and ethanol (2 mL) was stirred at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate). The residue was crystallized from ethyl acetate/hexane to give the title compound (13 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:21][OH:22].C([O-])(=O)C.[NH4+].C(O)C>C(OCC)(=O)C.C1CCCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:21][OH:22])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2cc(F)ccc2O)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CCO
Product: CC(=O)N1CCC(C(=NO)c2cc(F)ccc2O)CC1
Yield: 65.6 %

Procedure:
A mixture of 12.7 g of 1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidine, 6.6 g of hydroxylamine hydrochloride, 11.0 g of ammonium acetate and 200 ml of ethanol-ether was heated under reflux for 10 hrs. After cooling, most of the ethanol was removed under reduced pressure. The resultant suspension was diluted with water and extracted with dichloromethane. The dichloromethane was evaporated in vacuo to give an oil. The oil was dissolved in ethyl acetate and cyclohexane was added to precipitate a solid. The solid was recrystallized from ethyl acetate to give 8.8 g (65.4%) of product, mp, 181°-183°. The chromatogram showed 2 spots.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:16]([CH3:29])[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[Cl:28])=[O:18])[CH2:11][C@@H:12]([OH:15])[CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[C:32](OC)([CH3:34])[CH3:33].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:16]([CH3:29])[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[Cl:28])=[O:18])[CH2:11][C@@H:12]1[CH2:13][O:14][C:32]([CH3:34])([CH3:33])[O:15]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO[Si](C)(C)C(C)(C)C)C[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 1-((2S,4R)-1-(tert-butyldimethylsilyloxy)-4,5-dihydroxypentan-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea 1 (4.5 g, 10.0 mmol) in DMF (170 mL) were added 2,2-dimethoxypropane (12.45 mL, 100.0 mmol) and PPTS (0.050 g, 0.02 mmol) at 0° C. After 1 h the reaction was warmed up to RT and stirred for an additional 2.5 h. The crude reaction mixture was then added into a saturated aqueous solution of NaHCO3 (350 mL) and extracted with EtOAc (3×300 mL). Combined organic layers were washed with Brine (2×400 mL) and dried over MgSO4. The solution was then concentrated to give 1-((S)-1-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea, which was used without further purification. LRMS (M+H+) m/z 490.1.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[Br:29])[CH2:11][N:12]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[N:13]1[CH:17]=[N:16][N:15]=[CH:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:29][C:28]1[CH:27]=[CH:26][C:10]([CH2:11][N:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[N:13]2[CH:14]=[N:15][N:16]=[CH:17]2)=[CH:9][C:8]=1[OH:7]
Reactant: N#Cc1ccc(N(Cc2ccc(Br)c(OC3CCCCO3)c2)n2cnnc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: N#Cc1ccc(N(Cc2ccc(Br)c(O)c2)n2cnnc2)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared by adapting the method reported by Tafi et al.[Tafi,2002] with the following modifications. To a solution of 4-[(3-(tetrahydropyran-2-yloxy)-4-bromobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole (3.05 g, 6.71 mmol) in MeOH (60 mL) was added a catalytic amount of p-toluenesulfonic acid at 0° C. and the mixture was stirred (allowing to slowly warm to room temperature) overnight. The solvent was removed in vacuo and the residue dissolved in EtOAc (100 mL). The organic fraction was washed with Na2CO3 solution (1M aqueous solution, 3×50 mL), brine (3×50 mL) and dried (Na2SO4). The solvent was removed in vacuo and the pale yellow residue recrystallised from EtOH to give STX1216 as an off-white powder (1.48 g, 60%); δH (400 MHz, DMSO-d6) 5.00 (s, 2H), 6.72 (dd, J=8.3, 2.1, 1H), 6.76 (AA′BB′, 2H), 6.86 (d, J=1.8, 1H), 7.43 (d, J=8.0, 1H), 7.78 (AA′BB′, 2H), 8.81 (s, 2H), 10.32 (s, 1H—exchanges with D2O); δC (100 MHz, DMSO-d6) 57.08 (CH2), 103.32, 109.42 114.07 (2×CH), 116.66 (CH), 119.51 (CH), 120.90 (CH), 133.54 (2×CH), 134.45 (2×CH), 136.14, 143.90, 151.82, 154.60; LRMS (FAB+) m/z (rel. intensity) 372.1 (94, [C16H12N5O81Br+H], 370.1 (100, [C16H12N5O79Br+H]); LC-MS (ES−) TR=1.98 min, m/z 368.1 (C16H12N5O79Br—H), 370.1 (C16H12N5O81Br—H); HPLC tR=1.77 min (100%); HRMS (FAB+) Found 372.02789; C16H13N5O81Br requires 372.02830. Found: C, 51.6; H, 3.4; N, 18.9; C16H12N5OBr requires C, 51.9; H, 3.3; N, 18.9%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:45])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][O:43][CH3:44])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][O:43][CH3:44])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:45])[NH:16][C:9]=2[CH:10]=1
Reactant: COCCNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: COCCNc1nc(C)cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-{3-[2-(2-methoxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K51) (212 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (122 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:32])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:24]=[N:23][C:22]3[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][C:19]([Cl:31])=[N:18][C:17]=3[CH:16]=2)[CH:10]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:1]([O:4][CH2:5][O:6][C:7](=[O:32])[N:8]([C:40](=[O:42])[CH3:41])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:24]=[N:23][C:22]3[C:21]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[N:20][C:19]([Cl:31])=[N:18][C:17]=3[CH:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCOC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCOC(=O)N(C(C)=O)c1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a 100 mL round bottom flask, (((3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carbamoyl)oxy)methyl acetate (1.0 g, 0.0022 mol), triethylamine (0.6 mL, 0.0044 mol) N,N-dimethylpyridin-4-amine (0.0054 g, 0.000044 mol) and DCM (25 mL) were added. To the same flask was added acetic anhydride (2.67 g, 0.0264 mol). The reaction was continued at room temperature for 18 hour. Additional acetic anhydride (1.63 g, 0.0161 mol) was then added to the reaction mixture. The reaction was further continued at room temperature for 24 hours. The reaction mixture was diluted with DCM. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to provide the title compound (0.97 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 9.14 (d, J=2.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.53 (dd, J′=7.6 Hz, J″=0.8 Hz, 1H), 5.66 (s, 2H), 4.65-3.97 (br s, 4H), 3.80 (t, J=4.8 Hz, 4H), 2.55 (s, 3H), 2.03 (s, 3H). LC-MS (ESI): Calculated mass: 499.13; Observed mass [M+H]+: 499.8 (RT: 1.52 min).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.O.[OH-].[Na+]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(OCc2cccc(F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
(Aldrich data.) To a LiAlH4 (5.02 g, 132.0 mmol) suspension in THF (400 mL) was added dropwise a THF (30 mL) solution of 4-(3-fluorobenzyloxy)benzonitrile (10.00 g, 44.0 mmol) at 0° C. The mixture was stirred at room temperature (16 h) and H2O (4 mL) was added dropwise at 0° C. followed by an aqueous NaOH solution (2 mL, 15% w/w), and then H2O (4 mL). The mixture was stirred at room temperature (2 h), and the precipitate filtered through a Celite® pad and the pad washed with CH2Cl2. The filtrate was concentrated in vacuo to obtain a white solid (8.82 g, 86%): Rf=0.00 (hexanes/EtOAc 9/1); 1H NMR (CDCl3) δ 1.61 (br s, NH2), 3.79 (s, CH2NH2), 5.04 (s, CH2O), 6.90-7.04 (m, 3 ArH) 7.13-7.37 (m, 5 ArH); HRMS (M-NH2+) (ESI+) 215.088 [M-NH2+] (calcd for C14H12O+ 215.087).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([O:19]CC)=[O:18])[C:5]2=[O:22].Cl.C(O)(=O)C>O>[F:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 63.7 %

Procedure:
A mixture of 1.70 g of ethyl 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, 30 ml of concentrated hydrochloric acid, and 60 ml of acetic acid was heated under reflux for 1.5 hours. After allowing to cool, water was added to the reaction mixture. The precipitated crystals were collected by filtration, washed with water and ethanol, and dried. Recrystallization from a mixed solvent of ethanol and chloroform yielded 990 mg of the titled compound as a pale yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]#[N:9])[CH:4]=[N:3][CH:2]=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.[H-].[Na+]>CN(C=O)C>[CH:12]1([CH2:11][CH:7]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[C:8]#[N:9])[CH2:14][CH2:13]1
Reactant: N#CCc1cncnc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CC1CC1)c1cncnc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
A solution of 2-(pyrimidin-5-yl)acetonitrile (1.8 g, 15.1 mmol) in DMF (20 mL) was degassed and (bromomethyl)cyclopropane was added (2.04 g, 15.1 mmol). The reaction mixture was cooled to −10° C., NaH was added (720 mg, 18.1 mmol, 60% in mineral oil) in portions under N2 and stirred at the same temperature for 45 mins. The reaction mixture was quenched with sat. NH4Cl and extracted with EtOAc (30 ml×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purification by column chromatography on silica gel (petroleum ether: EtOAc=3:1) to give 3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile (2.25 g, yield: 85%).1H NMR (CDCl3 400 MHz): δ9.22 (s, 1H), 68.78 (s, 2H), 3.80 (t, J=8 Hz, 2H), 1.98-1.92 (m, 1H), 1.83-1.79 (m, 1H), 0.87-0.83 (m, 1H), 0.61-0.59 (m, 2H), 0.21-0.13 (m, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.NC1C=CC(C([NH:73][CH:74]2[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]2)=O)=CC=1OC>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:73][CH:74]4[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]4)=[O:52])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of HATU (221 mg, 0.55 mmol) in DMA (10 mL) was added to a mixture of the 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 242; 220 mg, 0.5 mmol), DIPEA (261 uL, 1.5 mmol) and 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 72 mg, 0.62 mmol) in DMA (10 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was retrieved from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave the title compound as a pale yellow amorphous solid. (154 mg, 58%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CN(C=O)C.[Cl-].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[N:24][C:25]2[N:29]([CH3:30])[CH:28]=[CH:27][N+:26]=2[CH3:31])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl-:8].[NH2:1][C:2]1[N:7]=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]=[N:24][C:25]3[N:26]([CH3:31])[CH:27]=[CH:28][N+:29]=3[CH3:30])=[CH:21][CH:22]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Cn1cc[n+](C)c1N=Nc1ccc(N)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc[n+](C)c1N=Nc1ccc(Nc2cc(Cl)nc(N)n2)cc1

Procedure:
0.164 g of 2-amino-4,6-dichloropyrimidine (0.001 mol) and 3 ml of dry DMF, 0.251 g (0.001 mol) of 2-(4-amino-phenylazo)-1,3-dimethyl-3H-imidazol-1-ium chloride and 0.138 g (0.001 mol) of potassium carbonate are charged to a fully equipped round-bottomed flask. The mixture is brought for 17 hours to 80° C. with stirring. After cooling, 4 ml of water are added and the precipitate is filtered off. 100 mg of a red powder containing the starting 2-(4-aminophenylazo)-1,3-dimethyl-3H-imidazol-1-ium chloride and the expected product are obtained. The latter, purified by preparative HPLC, has the following UV absorption characteristics:
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].CS([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[O:21])[CH2:15][CH2:14]1)(=O)=O>>[CH2:1]([S:5]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)=[O:21])[CH2:15][CH2:14]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: CCCCS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 66 %

Procedure:
Butylsulfonyl chloride (76 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (65 mg, 0.160 mmol, 66% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.78 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 4.19 (d, J=Hz, 1H), 3.82 (d, J=Hz, 1H), 3.73 (m, 1H), 3.18 (t, J=12.4 Hz, 1H), 2.82 (m, 1H), 2.78 (t, J=Hz, 1H), 1.80 (t, J=9.6, 2H), 1.43 (m, 2H), 0.97 (s, 6H).
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1.[CH3:27][NH:28][CH3:29]>C(O)C.CN(C=O)C.O>[CH3:27][N:28]([CH3:29])[CH2:26][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: CNC
Reactant: Cc1cccc(Nc2cc(Nc3cccc(OCC4CO4)c3)ncn2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1cccc(Nc2cc(Nc3cccc(OCC(O)CN(C)C)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Using an analogous reaction procedure to that described in Example 33, a mixture of 4-[3'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine, 33% dimethylamine in ethanol and DMF was stirred overnight at ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The product so obtained was washed with water and with brine, dried (MgSO4) and evaporated. The residue was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[3'-(3-dimethylamino-2-hydroxypropoxy)anilino]6-(3'-methylanilino)pyrimidine in 55% yield, m.p. 120°-122° C.;
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([C:14]23[CH2:20][CH:17]([CH2:18][CH2:19]2)[CH2:16][C:15]3([NH2:25])[C:21]([O:23]C)=[O:22])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].CO>[C:1]1([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([C:14]23[CH2:20][CH:17]([CH2:18][CH2:19]2)[CH2:16][C:15]3([NH2:25])[C:21]([OH:23])=[O:22])=[O:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1(N)CC2CCC1(C(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1(C(=O)O)CC2CCC1(C(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1)C2

Procedure:
A solution of N-phenylsulfonyl-(L)-prolyl-2-amino-2-norbornanecarboxylic acid, methyl ester (210 mg, 0.2 mmol) in 3 mL of 1:1 aqueous sodium hydroxide (1 M) and methanol was stirred at room temperature for 2 weeks. The reaction was quenched with concentrated hydrochloric acid (0.2 mL), and the resulting mixture was partitioned between saturated salt solution and ethyl acetate. The product was extracted with ethyl acetate and was purified by flash chromatography on silica gel eluted with 100:5:1 methylene chloride/methanol/acetic acid to give the product as a mixture of diastereomers.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:22]([F:24])[F:23])=[C:10]([CH:20]=1)[CH2:11][NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[C:34](O)(=[O:43])[C@@H:35]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[OH:36].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:22]([F:24])[F:23])=[C:10]([CH:20]=1)[CH2:11][NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:34](=[O:43])[C@@H:35]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[OH:36]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)F)cc1
Reactant: O=C(O)[C@H](O)C1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@H](O)C2CCCCC2)C(F)F)cc1
Yield: 36.8 %

Procedure:
EDC (0.0469 g, 0.24 mmol was added to a stirred mixture of N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-L-prolinamide (0.0691 g, 0.16 mmol), (R)-hexahydromandelic acid (0.0258 g, 0.16 mmol) and HOAT (0.0111 g, 0.08 mmol) in DMF (2.0 mL). After 2 h the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 10-70% ethyl acetate/hexanes gradient) to give N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-[(2R)-2-cyclohexyl-2-hydroxyethanoyl]-L-prolinamide (0.0332 g) as a white solid; LC-MS m/z=564.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[CH:7]=[C:8]1[C:12](=[O:13])[O:11][C:10]([CH3:14])=[N:9]1)[CH3:2].CC(C)=[O:23]>O>[C:10]([NH:9][C:8]([C:12]([OH:11])=[O:13])=[CH:7][C:6]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH3:20])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)(=[O:23])[CH3:14]
Reactant: CC(C)=O
Reactant: CCOc1ccc(C=C2N=C(C)OC2=O)cc1OCC
Solvent: O
Product: CCOc1ccc(C=C(NC(C)=O)C(=O)O)cc1OCC
Temperature: 25 °C

Procedure:
4-(3,4-Diethoxybenzylidene)-2-methyloxazol-5(4H)-one (100 g) is added to acetone (200 ml) and water (400 ml), and the mixture is heated under reflux for 3.5 hours. The mixture is evaporated to remove the acetone, and cooled to room temperature. The precipitates are collected by filtration, and washed with water to give N-acetyl-3-(3,4-diethoxyphenyl)dehydroalanine (99 g).