Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34].C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[C:26]([C:25]1[CH:29]=[CH:30][C:22]([CH:20]2[O:19][N:18]=[C:17]([C:12]3[N:13]=[C:14]([CH3:16])[N:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:31]=[CH:32][C:2]([F:1])=[C:3]([O:33][CH3:34])[CH:4]=4)=[O:9])[CH:11]=3)[CH2:21]2)=[CH:23][CH:24]=1)(=[O:28])[NH2:36]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(C(=O)O)cc4)C3)nc(C)n2)ccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(C(N)=O)cc4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
To a stirred solution of 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoic acid (0.1 g, 0.215 mmol) in DMF (10 mL) was added HATU (0.123 g, 0.323 mmol) and DIEA (0.055 g, 0.43 mmol). The reaction mixture was stirred at RT for about 10 min. Ammonia solution (3 mL) was added and the reaction mixture stirred for about another 2 h. The reaction mixture was diluted with ice cold water (20 mL). The solid which was obtained was filtered, washed with water and dried under vacuum to afford 6-(5-(4-carbamoylphenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.05 g), (50%) as an off white solid. LC/MS (Table 1, Method c) R1=4.48 min. MS m/z: 464.2 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:22]([NH2:25])=[N:23][OH:24])[CH2:9][C@@H:8]1[CH2:41][CH3:42])=[O:6])([CH3:3])[CH3:2].[C:43](OC(=O)C)(=O)[CH3:44]>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=2)[C:22]2[N:25]=[C:43]([CH3:44])[O:24][N:23]=2)[CH2:9][C@@H:8]1[CH2:41][CH3:42])=[O:6])([CH3:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(N)=NO)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Reactant: CC(=O)OC(C)=O
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2noc(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 80 °C

Procedure:
To (+/−)-cis-4-[N-(3,5-bis-trifluoromethyl-benzyl)-hydroxyguanidino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (80 mg, 0.13 mmol), add acetic anhydride (0.5 mL). Seal the tube and heat the reaction mixture at 80° C. overnight. Cool down the mixture and remove the solvents under reduced pressure. Add 2 N NaOH (2 mL) and ether to the crude material. Separate the layers, and extract the aqueous phase with ether. Dry the combined organic phase, filter, and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (32 mg, %). MS (ES+): 640 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=O)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH:11]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Solvent: c1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1NCc1ccccc1
Yield: 71 %

Procedure:
24.7 g of 1-benzyl-3-carboethoxy-4-pyrrolidone and 10.7 g of benzylamine were added to 100 ml of benzene, and then dehydrated with Dean-Stark distillation apparatus. The residual benzene was evaporated. The residue was dissolved in 200 ml of tetrahydrofuran, and then a small amount of methyl orange was added. To this was added methanol saturated with hydrogen chloride to adjust the pH to about 4, and then 7 g of sodium cyanoborohydride was added thereto. A solution of methanol saturated with hydrogen chloride was added dropwise to the reaction solution with stirring until the pink-color of the solution did not disappear. The reaction solution was basified with 15% aqueous caustic soda solution, and then the reaction mixture was diluted with ether, after which the aqueous layer was separated the aqueous layer was removed by addition of ether. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and then subjected to silica gel column chromatography (hexane:ethyl acetate, 5:1 (v/v)) to obtain 24 g of the desired compound (yield: 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH:17]1CP(C2C=CC=CC=2)C(C2C=CC=CC=2)(C2C=CC=CC=2)C1=C)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C1C(C(=O)OCC)CP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
4-Nitrobenzaldehyde (1 g) was dissolved in methylene chloride (20 ml), and the reaction system was cooled to 0° C. The solution was added with carboethoxy-methylenetriphenylphospholan (2.56 g) and stirred at 0° C. for 1 hour. The reaction system was concentrated under reduced pressure without any treatment, and the residue was purified by silica gel column chromatography (50 g, hexane:ethyl acetate=4:1) to obtain ethyl 3-(4-nitrophenyl)acrylate (1.27 g, 86%).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])C.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:28]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:7]([C:5](=[O:6])[C:4]([OH:3])=[O:27])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1ccccc1Br
Reactant: C#CCCCCCCCC
Product: CCCCCCCCC#Cc1ccccc1CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(=O)O

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl{(2-bromobenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate and dec-1-yne gave the title compound as a pale yellow oil. M−(LC/MS(ESI)): 472.0. HPLC (Condition A), Rt: 5.51 min (HPLC purity: 99.6%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.O.[NH2:22][NH2:23]>>[NH:22]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1)[NH2:23]
Reactant: NN
Reactant: Cn1cnc2c(NCCc3ccccc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(NCCc3ccccc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)phenethyl-amine and hydrazine monohydrate.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>ClCCl>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]
Reactant: N#Cc1cccc(CO)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc(COC2CCCCO2)c1
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
Add p-toluene sulphonic acid (2.11 g, 12.2 mmol) to a solution of 3-hydroxymethyl-benzonitrile (16.30 g, 122.4 mmol) and 3,4-dihydro-2H-pyran (51.5 g, 612 mmol) in dichloromethane (500 ml) and stir. After 90 minutes, pour reaction into saturated sodium bicarbonate, remove organics, dry with sodium sulfate, filter and concentrate to give a dark brown oil. Purify the residue by flash chromatography eluting with a gradient of 10-15% ethyl acetate:hexanes to yield the title product as a clear oil (16.20 g, 61%): 1H NMR (CDCl3) δ 1.53-1.91 (m, 6H), 3.56 (m, 1H), 3.88 (m, 1H), 4.53 (d, 1H), 4.72 (t, 1H), 4.81 (d, 1H), 7.45 (t, 1H), 7.58 (m, 2H), 7.69 (s, 1H)
Reaction SMILES: [NH2:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:15][N:16]([CH3:30])[C:17]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:13]1[C:14]2[CH:2]([NH:1][CH:20]3[CH2:19][CH2:18][C:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([N:16]([CH3:30])[CH3:15])[CH2:22][CH2:21]3)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
9-Aminofluorene (362 mg, 2 mmol) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 440 mg N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid which, for preparation of the hydrochloride, was dissolved in 2-butanone (10 ml), and 1.85 M ethanolic HCl (1.55 ml) was added. The mixture of N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (460 mg, m.p. 202-205° C.).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: COCC(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:15][C:2]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1
Reactant: Nc1ncccn1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1
Temperature: 95 °C
Reaction time: 24 h
Yield: 35.9 %

Procedure:
Add 2-bromo-1-(4-(trifluoromethyl)phenyl)propan-1-one (100 g, 0.356 mol), 2-aminopyrimidine (33.85 g, 0.356 mol), and sodium bicarbonate (59.8 g, 0.811 mol) to toluene (500 mL) at 25 to 30° C. Heat the mixture to 90 to 100° C. and stir for 24 hours. Thereafter cool the mixture to 40 to 45° C., and distill the title compound under reduced pressure. Cool the distillate to 25 to 30° C.; add water (1 L); and stir the mixture 4 hours. Filter the mixture collecting the solid, and then wash the solid with a 10% solution of MTBE (200 mL) in hexane. Dry the solid under vacuum at 45 to 50° C. for 12 hours to give the title compound (35.4 g, 35% yield). 1H NMR (300 MHz, CDCl3) δ 8.58 (q, 1H), 8.24-8.26 (d, J=6.6 Hz, 1H), 8.00-8.02 (d, J=8.1 Hz, 2H), 7.72-7.75 (d, J=8.4 Hz, 2H), 6.92-6.96 dd, J=3.9 Hz and 4.2 Hz, 1H), 2.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:23][CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[BH4-].[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:23][CH:24]2[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 61, 30.0 mg, 0.064 mmol) in methanol (0.5 mL) was treated with sodium borohydride (6.03 mg, 0.16 mmol). The reaction mixture was stirred at 25° C. for 5 min. The reaction was then diluted with ethyl acetate (5 mL) and quenched by the dropwise addition of water. The reaction was then diluted with more water (5 mL) and concentrated in vacuo to remove methanol. The resulting slurry was extracted with ethyl acetate (3×5 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12S, Silica, 3/7 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-hydroxy-cyclohexyl)-propionamide (29.0 mg, 96.3%) as a light yellow foam: EI-HRMS m/e calcd for C20H23Cl2N3O4S (M+H)+ 472.0859, found 472.0866.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]#[N:21])=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25].N>CN(C=O)C>[Cl:25][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:12][C:11]=1[C:20]#[N:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(-c2ccncc2)c(-c2ccc(F)cc2)nc1O
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccncc2)c(-c2ccc(F)cc2)nc1Cl
Yield: 55.4 %

Procedure:
A mixture of 2-(4-fluorophenyl)-6-hydroxy-3,4′-bipyridine-5-carbonitrile (6.57 g, 22.5 mmol, obtained in reference example 10), POCl3 (26.3 mL, 287.5 mmol) and DMF (0.37 mL) was heated to reflux under argon atmosphere for 2 h. It was cooled with an ice bath and basified by adding 30% aqueous NH3. The precipitate obtained was filtered and washed with water. The product was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 3.86 g of the desired product as a yellow solid (yield: 55%).
Reaction SMILES: [C:1]1([C@@:7]([NH2:19])([CH3:18])[CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:18][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[C:28](=[O:30])[NH:19]1
Reactant: Cc1cccc(NCC[C@@](C)(N)c2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCC(C)(c3ccccc3)NC2=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
To a solution of (R)-3-phenyl-N1-m-tolylbutane-1,3-diamine (50 mg, 0.2 mol) and Et3N (60 mg, 0.6 mmol) in CH2Cl2 (3 mL) was added triphosgene (24 mg, 0.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and concentrated. The residue was purified by preparative HPLC to give 4-methyl-4-phenyl-1-m-tolyl-tetrahydro-pyrimidin-2-one (8 mg, 14%). LC-MS Method 1 tR=1.13 min, m/z=281; 1H NMR (CDCl3): 1.65 (s, 3H), 2.15-2.23 (m, 1H), 2.25 (s, 3H), 2.27-2.47 (m, 1H), 3.20-3.22 (t, 1H), 3.37-3.40 (d, 1H), 6.89-6.92 (m, 2H), 6.99-7.01 (m, 1H), 7.15-7.17 (m, 1H), 7.25-7.27 (m, 1H), 7.7.31-7.38 (m, 4H), 7.83 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: Nc1cccc(C(=O)O)c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N)c1Cl
Yield: 92 %

Procedure:
A mixture of 3-amino-2-chlorobenzoic acid (500 mg, 2.91 mmol), conc. sulfuric acid (6 mL), and methanol (150 mL) was heated under reflux for 24 hours, and placed under reduced pressure to distill the solvent off. The residue was neutralized by addition of aqueous saturated sodium hydrogen carbonate. The neutralized mixture was extracted with toluene, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. There was obtained 497 mg (yield 92%) of the desired compound in the form of pale brown oil.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([O:10]C2C=CC(Cl)=CC=2)=O)=[N:5][N:4]=1)#[N:2].[Cl:18]C1C=CC(O)=CC=1>>[C:1]([C:3]1[S:7][C:6]([C:8]([Cl:18])=[O:10])=[N:5][N:4]=1)#[N:2]
Reactant: N#Cc1nnc(C(=O)Oc2ccc(Cl)cc2)s1
Reactant: Oc1ccc(Cl)cc1
Product: N#Cc1nnc(C(=O)Cl)s1

Procedure:
4-Chlorophenyl 5-cyano-1,3,4-thiadiazole-2-carboxylate can be prepared by reacting 4-chlorophenol (12.9 g.) with 17.4 g. 5-cyano-1,3,4-thiadiazole-2-carbonyl chloride as in Example 1 to give 22 g. light tan product.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([OH:15])[CH2:13][OH:14])=[C:10]([CH3:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:17])=[N:7]2.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>ClCCl.N1C=CC=CC=1>[C:20]([O:14][CH2:13][C@H:12]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:16])[N:7]=[C:6]([CH3:17])[CH:5]=[CH:4]2)[OH:15])(=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18]
Reactant: Cc1ccc2c(Br)c([C@H](O)CO)c(C)cc2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(Br)c([C@H](O)COC(=O)C(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-1-(5-bromo-2,7-dimethylquinolin-6-yl)ethane-1,2-diol (290 mg, 0.98 mmol) in dichloromethane (12 mL) and pyridine (2 mL) was added trimethyl acetylchloride (0.24 mL, 1.97 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, and quenched with slow addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calc'd for C18H23BrNO3: 380.1; Found: 380.2.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[CH:51]=[CH:50][NH:49][C:48]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[CH:51]=[CH:50][NH:49][C:48]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Reactant: O=C(O)c1[nH]ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 3-chloro-1H-pyrrole-2-carboxylic acid (0.0289 g, 0.199 mmol) nd diisopropylethylamine (0.052 mL, 0.298 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.018 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.80 (br. s., 1H), 8.29-8.40 (m, 1H), 7.91-8.04 (m, 2H), 7.57-7.69 (m, 3H), 7.51 (dd, 1H), 7.35 (t, 2H), 6.93 (t, 1H), 6.52 (d, 1H), 6.19 (t, 1H), 4.54 (d, 2H). ES MS: m/z 429 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Oc1ccc(F)cc1F
Reactant: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: NS(=O)(=O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 72.6 %

Procedure:
A mixture of Example 86a (0.543 g, 2 mmol), 2,4-difluorophenol (0.390 g, 3.00 mmol), and cesium carbonate (1.955 g, 6.00 mmol) in DMSO (10 mL) was heated at 110° C. for 16 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (3:2 ethyl acetate/hexanes) on silica gel to give the title compound (0.53 g, 1.451 mmol, 72.6% yield).