Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=1.O>C(O)C>[Br:21][C:17]1[CH:18]=[C:19]([CH3:20])[C:14]2[N:15]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[N:13]=2)[CH:16]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: Cc1cc(Br)cnc1N
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1cn2cc(Br)cc(C)c2n1
Temperature: 80 °C
Yield: 54.1 %

Procedure:
A mixture of 2-bromo-2′-methoxyacetophenone (0.500 g, 2.183 mmol) and 2-amino-5-bromo-3-methylpyridine (0.408 g, 2.183 mmol) in ethanol (8 mL) was heated to 80° C. for 16 hours in a pressure vessel. A yellow thick precipitate formed. Water was added and the solid was extracted with ethyl acetate (some DCM and MeOH were added to help in the dissolution). The organic extracts were then washed with brine, dried over Na2SO4, filtered and concentrated and the residue was purified by silica gel chromatography (Biotage SNAP 100 g, 10 to 20% ethyl acetate in hexanes) to give 220 (0.375 g, 1.182 mmol, 54.2% yield) as a white solid. LRMS (ESI): calc. 316.02 found 317.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Nc1c(Cl)cccc1Cl
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
2,6-Dichloroaniline (2.84 g, 17.5 mmol) was dissolved in DMSO (5 mL) and 60% NaH (0.60 g, 15 mmol) was added. The mixture was stirred 30 min and then 2-chloro-5-nitrobenzonitrile (0.91 g, 5.0 mmol) in DMSO (5 mL) was added. The reaction darkened and warmed to 50°. After cooling to 23° the reaction was diluted with EtOAc (200 mL) and washed with H2O (3×), satd. aq. NaCl, and dried (Na2SO4), and concentrated to afford 1.45 g (94%) of the title compound as an ivory colored powder. 1H NMR (400) MHz. δ: 8.49 (finely split doublet, 1), 8.20 (dd, 1), 7.51 (d,2), 7.34 (d, 2), 6.41 (d, 1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.Cl.[CH2:16]([S:18]([N:21]1[CH2:25][CH2:24][N:23]([C:26](Cl)=[O:27])[C:22]1=[O:29])(=[O:20])=[O:19])[CH3:17]>O1CCOCC1>[CH2:16]([S:18]([N:21]1[CH2:25][CH2:24][N:23]([C:26]([NH:14][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[C:11]([OH:13])=[O:12])=[O:27])[C:22]1=[O:29])(=[O:20])=[O:19])[CH3:17]
Reactant: NC(C(=O)O)c1ccc(Cl)cc1
Reactant: CCS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(C(=O)NC(C(=O)O)c2ccc(Cl)cc2)C1=O

Procedure:
Sufficient concentrated sodium hydroxide solution just to dissolve the acid was added to a suspension of 11.0 parts by weight of p-chloro-α-aminophenylacetic acid in 110 parts by volume of 50% strength aqueous dioxane. Dilute hydrochloric acid was then added with stirring until a pH of 7.5-8.0 was reached. 13.0 parts by weight of 3-ethylsulphonyl-imidazolidin-2-one-1-carbonyl chloride were then added in portions at about 0° C and the pH of the mixture was maintained at 7.5-8.0 by means of dilute sodium hydroxide solution. Thereafter the mixture was stirred further for as long as an occasional addition of sodium hydroxide solution was still necessary to maintain the pH of 7.5-8.0. The bulk of the dioxane was then removed in vacuo at pH 6.5, about 200 parts by volume of water were added, the mixture was extracted once with ether at pH 9.0 (the ether extract being discarded) and covered with fresh ether, and the pH was brought to 0.5 with stirring. The organic phase was then separated off, washed, dried and completely evaporated in vacuo. The residue was dissolved in hot ethyl acetate; thereafter the same amount of benzene and petroleum ether was added until there is turbidity which (only just) disappears again, and the mixture was left to crystallize.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH:9]1C(O)=O)([O:3][C:4](C)(C)[CH3:5])=[O:2].Cl.C(OC(=O)[C@H](CS)N)C.C(N(CC)CC)C.BrC(Br)C>C1COCC1>[CH2:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1)=[O:2])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCSCC1C(=O)O
Agent: CC(Br)Br
Agent: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCSCC1
Reaction time: 1 h
Yield: 87 %

Procedure:
4-Boc-thiomorpholine-3-carboxylic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: To THF was added cysteine ethyl ester hydrochloride (1.15 g, 6.18 mmol), triethylamine (4.17 mL, 30 mmol) and dibromoethane (2.51 mL, 6.2 mmol). After stirring for 1 hour and refluxing for 16 hours, the solids were removed by filtration. The solvent was removed in vacuo and the residue was chromatographed on silica to give thiomorpholinecarboxylic acid ethyl ester (0.94 g, 87%). The ester (15.3 g, 95 mmol) was dissolved in dioxane/water (1/1) and di-t-butyldicarbonate (24 g, 110 mmol) and LiOH were added. After stirring for 3 hours, the solvent was removed in vacuo and the pH was adjusted to 3 with KHSO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent was removed in vacuo to give 17.4 g (78%) 4-Boc-thiomorpholine-3-carboxylic acid: 1H NMR (CDCl3) δ 1.45 (m, 9), 2.45 (m, 1), 2.71 (m, 1), 2.93 (m, 1), 3.10 (m, 1), 3.29 (m, 1), 4.11 (m, 1), 4.19 (m, 1), 5.20 (m, 1).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.C(O)(C)C.C(=O)=O.[CH2:14]([O:21][C:22]([O:24][CH:25]1[CH2:34][CH2:33][C:32]2[N:31]=[CH:30][C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:28](O)[C:27]=2[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:22]([O:24][CH:25]1[CH2:34][CH2:33][C:32]2[N:31]=[CH:30][C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:28]([Cl:4])[C:27]=2[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cnc2c(c1O)CC(OC(=O)OCc1ccccc1)CC2
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(c1Cl)CC(OC(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (1.82 g) is added to 100 mL of DMF dropwise under stirring and cooling (isopropanol-dry ice) maintaining the temperature below -20°. Stirring is continued for 30 minutes at the same temperature. To the mixture, 2.66 g of ethyl 6-benzyloxycarbonyloxy-4-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate is added in one portion, and stirring is continued for 2 hours at -30° to -20°, then at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is taken up in CH2Cl2, washed with saturated NaHCO3, dried (MgSO4) and evaporated to leave an oil which is purified by flash chromatography on a silica gel column obtaining ethyl 6-benzyloxycarbonyloxy-4-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH:36]4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH3:39][O:40]CCN>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:40][CH3:39])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Reactant: COCCN
Product: COCCNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 2-methoxyethylamine instead of cyclopropylmethylamine. LC-MS: (M+1=533, obsd.=533).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Clc1cc(-c2ccccc2)ncn1
Yield: 34 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 3.35 g of 4,6-dichloropyrimidine, 3.02 g of phenylboronic acid, 1.7 mL of tricyclohexylphosphine (abbreviation: Cy3P), 14.7 g of cesium carbonate, 0.31 g of tris(dibenzylideneacetone)palladium(0) (abbreviation: Pd2(dba)3), and 30 mL of dioxane, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 120 W) for 60 minutes for reaction. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane and hexane as a developing solvent in a volume ratio of 1:1, to give 4-chloro-6-phenylpyrimidine (light yellow powder, 34% in yield). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is shown in (b-1) given below.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[CH3:3].[NH2:26][C:27]1[N:32]=[C:31](Cl)[C:30]([C:34]#[N:35])=[C:29]([CH3:36])[N:28]=1.C(N(CC)CC)C>CS(C)=O>[NH2:26][C:27]1[N:32]=[C:31]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15]2)[CH3:3])[C:30]([C:34]#[N:35])=[C:29]([CH3:36])[N:28]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1C1CCN(C(=O)OC(C)(C)C)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 85 °C

Procedure:
To a 25 mL pear flask were added the mixture of diastereomers of tert-butyl 3-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidine-1-carboxylate (0.057 g, 0.17 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.042 g, 0.25 mmol) in DMSO (1 mL). Triethylamine (0.069 mL, 0.50 mmol) was added and the mixture was heated to 85° C. for 14 hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by liquid chromatography (SiO2, 25-100% EtOAc/hexanes). The product-containing fractions from two different peaks were pooled separately and concentrated in vacuo to give the title diastereomers. Peak 1 (shorter retention time, 19 mg, 24%): 1H NMR (400 MHz, CDCl3) δ ppm 0.69-0.85 (m, 5H), 1.32-1.51 (m, 22H), 2.15-2.40 (m, 8H), 3.33-3.49 (m, 2H), 3.52-3.86 (m, 8H), 4.70 (dd, J=10.74, 7.45 Hz, 1H), 5.27 (br s, 1H), 5.62-5.75 (m, 1H), 5.82-5.96 (m, 2H), 6.60 (br s, 2H), 6.73 (d, J=8.84 Hz, 1H), 7.19 (s, 2H), 7.33-7.45 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C25H32N8O2, 477. found 477. Peak 2 (longer retention time, 41 mg, 52%): 1H NMR (400 MHz, CDCl3) δ ppm 0.66-0.90 (m, 3H), 1.39-1.52 (m, 15H), 1.88-2.07 (m, 3H), 2.21-2.40 (m, 5H), 3.30-3.89 (m, 10H), 5.02-5.20 (m, 2H), 5.65 (t, J=6.44 Hz, 1H), 6.61 (d, J=3.03 Hz, 1H), 7.14-7.24 (m, 2H), 7.28-7.46 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C25H32N8O2, 477. found 477.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])=[CH:7][CH:6]=1.C(OC([N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][C:48](O)=[O:49])[CH2:42][CH2:41]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:48](=[O:49])[CH2:47][CH2:46][N:43]2[CH2:44][CH2:45][NH:40][CH2:41][CH2:42]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccc(CC(=O)OC)cc3)C(=O)CCN3CCNCC3)c2n1

Procedure:
The product of example 1, step (ix) (0.27 g) was dissolved in DCM (10 ml) and treated with 4-(2-carboxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.16 g) and HATU (0.23 g). The reaction was stirred at rt for 16 h, before 2 mls of TFA added. The mixture was purified by RPHPLC, to give the title compound. Yield 3 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A 1 L single-necked round-bottomed flask was charged with 7 (61.4 g, 0.172 mol), benzyl amine (55.6 g, 0.519 mol, 3 eq), and anhydrous anisole (300 g) and then stirred at reflux until reaction was essentially complete (23 h, 165° C. oil bath temperature; internal temperature was 147° C.) and then allowed to cool to near room temperature. A portion (1 mL) of the reaction mixture was diluted with toluene (1 mL) resulting in the complete crystallization of that portion. This seed was then added to the reaction mixture and allowed to stand until the whole reaction mixture had crystallized to a single block. Toluene (150 mL) was added and the mixture swirled to break up the solid. Heptane/toluene (1:1, 100 mL) was added and the solid mixture broken up further. Finally, heptane (50 mL, then 25 mL) was added and the mixture broken up even further, allowing to stand an additional 30 min before filtering the solid. Filtration of the solid, washing with 2:1 toluene/heptane (300 mL), 1:2 toluene/heptane (300 mL), and then heptane (2×300 mL), and then drying (air, then high vac) gave 60.16 g (yield of 81%) of title product as a white solid (≧98.9% AUC). Another 2.5 g of less pure (97.4%) material was obtained from the mother liquors.
Reaction SMILES: ClC(N(C)C)=C(C)C.[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH3:23])[C:18]([OH:20])=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CC=CC=1.[CH3:30][C:31]1[N:35]=[C:34]([NH2:36])[S:33][N:32]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH3:23])[C:18]([NH:36][C:34]1[S:33][N:32]=[C:31]([CH3:30])[N:35]=1)=[O:20])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: Cc1nsc(N)n1
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1nc(C)ns1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.521 mL, 11.50 mmol) in DCM (2 mL) was added dropwise to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropanoic acid (Intermediate C4c) (2.45 g, 10.45 mmol) in DCM (10 mL) over a period of 1 minute under nitrogen. The resulting pale yellow solution was stirred at ambient temperature for 30 minutes Anhydrous pyridine (1.262 mL, 15.68 mmol) was added in one portion (solution turns deeper yellow) followed by 3-methyl-1,2,4-thiadiazol-5-amine (CAS no. 17467-35-5) (1.204 g, 10.45 mmol) in DCM (3 mL) dropwise over a period of 1 minute. The resulting solution was stirred at ambient temperature for 1 hour. 1M citric acid (50 mL) added and extracted with EtOAc (50 mL). Organic phase washed with water (25 mL) and brine (25 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane to afford (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (390 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 0.11 (6H, dd), 0.89 (9H, s), 2.49 (3H, s), 3.30 (3H, s), 3.61 (2H, t), 4.46 (1H, dd), 9.75-9.90 (1H, s); m/z (ESI+) (M+H)+=332.30; HPLC tR=2.77 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[C:52]([NH2:57])[CH:51]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>O1CCCC1>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[C:52]([NH:57][C:18](=[O:20])[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=3)[CH:51]=2)[CH2:47][CH2:48]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1N
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(F)c(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid (0.200 g) in tetrahydrofuran (2 ml) at 0° C. was added triethylamine (110 ul) followed by dropwise addition of isobutylchloroformate (100 ul). After stirring for 1 hr, triethylamine (150 ul) was added followed by 4-(3-amino-4-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.234 g) in tetrahydrofuran (2 ml), and the reaction warmed to room temperature and then heated at 58° C. overnight. After cooling to room temperature, the reaction mixture was filtered through Celite, the filtrate collected and the solvent removed in vacuo. Purification by NPHPLC (0-5% MeOH in CH2Cl2) afforded the sub-title compound as a pale yellow solid (0.300 g).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:37]2[C:38]([C:43]3C=C(C)C=CC=3)=[N:39]OC=2C)=NC=1>>[CH:38]([NH:39][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:43])[CH3:37]
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(C)c3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(C)cc3)noc2C)nc1
Product: Cc1ccc(-c2noc(C)c2COc2ccc(C(=O)NC(C)C)cn2)cc1
Yield: 78 %

Procedure:
As described for example 250, 6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (250 mg, 0.73 mmol) was converted, instead of 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (210 mg, 78%) which was obtained as a white solid. MS: m/e=366.3 [M+H]+.
Reaction SMILES: COC[N:4]1[C:13](=[O:14])[C:12]2[C:11]3[CH:15]=[C:16]([CH2:19][O:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:32].Cl>C1COCC1.O>[CH3:32][C:5]1[NH:4][C:13](=[O:14])[C:12]2[C:11]3[CH:15]=[C:16]([CH2:19][O:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc3ccc4nc(C)n(COC)c(=O)c4c3c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccc3ccc(COc4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 4-((1,2-dihydro-2-methoxymethyl-3-methyl-1-oxo-benzo[f]quinazolin-9-yl)methoxy)benzoate in THF:1N HCl: concentrated HCl (15:10:1, 26 ml) was stirred at 60° C. overnight. The resulting suspension was diluted with water, concentrated in vacuo to remove the THF, and chilled in an ice bath. The solid was filtered, washed with water, and dried in vacuo at 100° C. The resulting ester was dissolved in 1N NaOH (10 ml) and ethanol (~ 3 ml) and stirred at 60° C. for 4 hours. The solution was acidified with concentrated HCl to pH 1.5 and the resulting precipitate filtered and dried in vacuo at 110° C. to give 4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoic acid (0.195 g). 1H NMR (DMSO-d6, 300 MHz) δ: 2.59 (s, 3H, CH3), 5.46 (s, 2H, CH20), 7.17 (d, J=9 Hz, 2H, Ar), 7.80 (overlapping d, J=9 Hz, 2H, Ar), 7.91 (d, J=9 Hz, 2H, Ar), 8.16 (d, J=8 Hz, 1H, Ar), 9.85 (s, 1H, Ar).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[C:18]([F:30])[CH:17]=2)[CH2:11]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:30])[CH:17]=2)[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (0.15 mL) was added to a solution of 5-(S)-aminomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one (0.325 g, 1.0 mmol) and pyridine (0.25 mL) in DCM (4.0 mL). The mixture was stirred at r.t. for 4 h, and solvent was removed under vacuum. The resulted 5-(S)-acetamidomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazoli-dine-2-one was washed with water (2×3 mL), diethyl ether (3 mL), and dried under vacuum. 50% TFA in DCM (3 mL) was added, and the mixture was kept at r.t. for 1 h. Solvents were removed under vacuum, and the residue distributed between ethyl acetate (40 mL) and saturated aq. sodium bicarbonate (20 mL). Organic layer was washed with aq. sodium bicarbonate, water, brine, dried (MgSO4). Solvent was removed under vacuum to afford the product as a white solid. Yield 0.25 g (95%). MS (m/z): [M+H]+=268.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCCC.C(O)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1

Procedure:
The e.e. of N-benzyloxycarbonyl-3-hydroxypyrrolidine was measured by analytical HPLC with a chiral column [Chiralpak AS (Daicel), 250 mm×4.6 mm; eluent: hexane/isopropanol (100:4); flow rate: 1 ml/min; detection wavelength: 210 nm; retention times: 32.9 min for the (S)-form and 36.7 min for the (R)-form]. (R)-N-benzyloxycarbonyl-3-hydroxypyrrolidine was obtained in as 85% e.e.