Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.[CH3:26]COCC>C1COCC1>[C:1]([N:8]([C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH3:11])[CH3:26])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(2R,3R)-3-(N-Boc-N-methylamino)-2-(-tert-butyldimethylsilyloxy)-pent-4-yne was synthesized according to Method Y above by the treatment of (2R,3R)-N-Boc-3-amino-2-(-tert-butyldimethylsilyloxy)-pent-4-yne (400 mg, 1.27 mmol) (Example 117B) with NaH (36 mg, 1.52 mmol) and MeI (360 mg, 2.54 mmol) in THF (30 mL). The product was obtained after silica gel column chromatography with a 0-10% Et2O in hexanes gradient. (Yield 370 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH:16]([F:18])[F:17])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH:20]([CH3:24])[C:21]([OH:23])=[O:22]>>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH:16]([F:18])[F:17])=[CH:4][C:5](=[O:8])[N:6]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:7]=1
Reactant: CC(Br)C(=O)O
Reactant: O=c1cc(-c2cc(Cl)ccc2C(F)F)c(Cl)c[nH]1
Product: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
118 mg (0.41 mmol) of 5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]pyridin-2(1H)-one and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 35° C. Yield: 112 mg (76% of theory)
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:23]([O:25][C:26](=[O:49])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]2[O:38][N:37]=[C:36]([CH2:39][O:40]C3C=CC(OC)=CC=3)[N:35]=2)=[CH:29][CH:28]=1)[CH3:24]>C(#N)C.O>[CH2:23]([O:25][C:26](=[O:49])[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]2[O:38][N:37]=[C:36]([CH2:39][OH:40])[N:35]=2)=[CH:31][CH:32]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(Cc2nc(CO)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 528 %

Procedure:
Add half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol) to a solution of 4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester (193 mg, 0.52 mmol) in acetonitrile (9 mL) and water (2.3 mL) at room temperature. Stir the reaction mixture at room temperature for one hour and add the second half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol). Stir at room temperature for an additional hour, dilute the reaction is with saturated aqueous sodium hydride CO3, stir for 5 minutes, dilute with water, and extract with ethyl acetate (3×). Wash the combined organic layers with brine, dry over MgSO4, and concentrate. Purify the residue by flash column chromatography using 50% ethyl acetate/hexane to give the title compound (720 mg, 81%). LC-MS (m/e): 263 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[SH:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][S:43][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)c(Oc2ccccc2)c1
Temperature: 95 °C
Yield: 69.1 %

Procedure:
A 1 L flask was charged with tert-butyl 4-(5-(5-bromo-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (Example 4, Step D, 24.4 g, 45.8 mmol), N-ethyl-N-isopropylpropan-2-amine (16.0 mL, 91.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (1.33 g, 2.29 mmol), and dioxane (450 mL). Nitrogen was bubbled through the solution for 30 minutes. Methyl 3-mercaptopropanoate (5.46 mL, 50.4 mmol) and Pd2dba3 (1.05 g, 1.15 mmol) were added and the reaction was heated at 95° C. overnight. The reaction was cooled to ambient temperature and the resultant solids were filtered through celite. The filtrate was concentrated and purified on silica (30 to 40% EtOAc in hexanes) to afford tert-butyl 4-(5-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (18.1 g, 69.1% yield) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:9][OH:10])[NH2:8])[N:6]=1.[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](Cl)=O>>[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[O:10][N:9]=[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)[N:8]=1
Reactant: Cc1nc(C(N)=NO)cs1
Reactant: O=C(Cl)c1sccc1Cl
Product: Cc1nc(-c2noc(-c3sccc3Cl)n2)cs1

Procedure:
The title compound was prepared from 2-methyl-thiazole-4-amidoxime (24.6 mg, 0.156 mmol) and 3-chloro-thiophene-2-carbonyl chloride (28.7 mg, 0.159 mmol) similar to Example 16, and yielded 18.2 mg (40%) of white solid. 1H NMR (CDCl3): 8.03 (s, 1H), 7.61 (d, J=5.49 Hz, 1H), 7.13 (d, J=5.22 Hz, 1H), 2.84 (s, 3H).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cu](C#N)[C:19]#[N:20].N(OCCC(C)C)=O>C(#N)C.C(OCC)(=O)C>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([C:19]#[N:20])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: N#C[Cu]C#N
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.50 g, 2.02 mmol) in acetonitrile (50 mL) was added copper cyanide (0.36 g, 4.04 mmol) and isoamyl nitrite (0.54 mL, 4.04 mmol). The reaction mixture was heated to reflux for 1 hour, cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford N-benzyl-2-cyano-4-methylthiazole-5-carboxamide in 29% yield (0.15 g): 1H NMR (300 MHz, CDCl3) δ 7.48-7.18 (m, 5H), 6.87 (br s, 1H), 4.49 (d, J=5.8 Hz, 2H), 2.69 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][C:26]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[CH:27][C:28]=3C)=[O:23])=[CH:17][C:16]=2[O:37][CH3:38])[CH2:9]1)=O)(C)(C)C.[C:39]([Li])(C)(C)[CH3:40].CCCCC.CN(C)C=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O1CCCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:26]2[S:25][C:24]3[C:22](=[O:23])[N:21]([C:18]4[CH:19]=[CH:20][C:15]([O:14][C@@H:10]5[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]5)=[C:16]([O:37][CH3:38])[CH:17]=4)[CH:39]=[CH:40][C:28]=3[CH:27]=2)=[CH:31][CH:32]=1
Reactant: [Li]C(C)(C)C
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2C)ccc1O[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCC
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O[C@@H]1CCCNC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
Dissolve (R)-3-(4-{[5-(4-chloro-phenyl)-3-methyl-thiophene-2-carbonyl]-amino}-2-methoxy-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.63 g, 4.72 mmol) in tetrahydrofuran (35 mL) under argon and cool to −78° C. Add 1.7 M tert-butyllithium in pentane (6.1 mL, 10.38 mmol) while maintaining the temperature below −70° C. Stir the solution at −78° C. for 20 min. Add N,N-dimethylformamide (2.68 mL, 34.46 mmol) to the solution maintaining temperature below −70° C. Remove the cooling bath after 5 min and stir the reaction for 30 min. Quench the reaction with saturated aqueous ammonium chloride (20 mL). Dilute the mixture with water (10 mL) and extract with ethyl acetate (3×30 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo. Dissolve the residue in 30 mL of ethyl acetate and add p-toluenesulfonic acid (1.41 g, 7.08 mmol). Heat the mixture at reflux overnight, cool, and dilute with water (30 mL). Make the mixture basic with 1 N NaOH and extract with ethyl acetate (3×40 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo. Purify by chromatography (dichloromethane to 7% 2 M ammonia in methanol/dichloromethane) to afford 0.77 g (35%) of 2-(4-chloro-phenyl)-6-[3-methoxy-4-((R)-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridine-7-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](CC=O)[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg]Br>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCOC1(C)C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (12.0 g; CAS 147959-19-1) in dry diethyl ether (200 ml) under an argon atmosphere at room temperature was added dropwise a solution of methylmagnesium bromide in diethyl ether (49.3 ml, 3 M solution) and stirring continued overnight. The reaction mixture was then quenched by careful addition of water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→50:50) to give (S)-4-(R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (5.89 g) from fractions eluting first and (S)-4-(S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4.07 g) from fractions eluting later, both compounds as light yellow oils. (S)-4-(R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.60 (1H, br. D, J=3.3 Hz), 4.23 (1H, m), 4.00 (1H, dd, J=8.7 & 5.4 Hz), 3.71 (1H, m), 3.65 (1H, d, J=8.7 Hz), 1.76 (1H, td, J=11.4 & 2.1 Hz), 1.61-1.46 (16H, m), 1.20 (3H, d, J=6.3 Hz). (S)-4-(S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.13 (1H, m), 3.98 (1H, m), 3.85-3.60 (2H, m), 2.50 (1H, br. s), 1.80 (1H, m), 1.60-1.49 (16H, m), 1.22 (3H, d, J=6.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]([CH3:17])=[CH:7][N:6]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]([CH3:17])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)C=Cc1cc(C)cnc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(C)cnc1C(=O)OC
Yield: 89.5 %

Procedure:
3-(2-Methoxycarbonyl-vinyl)-5-methyl-pyridine-2-carboxylic acid methyl ester (2.58 g, 10.97 mmol) was dissolved in MeOH (100 ml) and hydrogenated at rt with Pd/C (10%, Engelhard 4505, 1.20 g) and 1.0 bar H2 for 1 h. The reaction was filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica (hex to hex/EtOAc 2/3 in 40 min) to give the product as colorless oil (2.33 g, 90%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.34 (s, 1H), 7.65 (s, 1H), 3.84 (s, 3H), 3.58 (s, 3H), 3.03 (t, 2H), 2.63 (t, 2H), 2.33 (s, 3H); LCMS RtI=2.786 min; [M+H]+=238.0.0]
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH:10]=2)=[O:5])C.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[CH2:21]([NH:20][C:18](=[O:19])[NH:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[N:7]=[CH:8]2)=[CH:13][CH:12]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: CCOC(=O)c1ncc2cc(NC(=O)NCc3ccccc3)ccc2c1O
Product: O=C(O)CCNC(=O)c1ncc2cc(NC(=O)NCc3ccccc3)ccc2c1O

Procedure:
3-{[7-(3-Benzyl-ureido)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 7-(3-Benzyl-ureido)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(b) using beta-alanine. MS ESI(−) m/e: 407.0882 (M−1).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10]([N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19])(=[O:12])[NH2:11]>>[C:17]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:18])/[CH:16]=[CH:15]\[C:14](=[O:19])[NH:13][C:10](=[O:12])[NH2:11]
Reactant: NC(=O)N1C(=O)C=CC1=O
Reactant: CCCCC(CC)CO
Product: CCCCC(CC)COC(=O)/C=C\C(=O)NC(N)=O
Yield: 95 %

Procedure:
The addition of 2-ethylhexanol to N-carbamylmaleimide under the conditions of Example C afforded a 95% yield of 2-ethylhexyl maleurate. M.P.: 73°-6° C.; 1H NMR (CDCl3): δ10.6 (br s, 1H), 8.2 (br s, 1H), 6.3 (m, 2H), 5.8 (br s, 1H), 4.2 (m, 2H), 1.6 (m, 1H), 1.3 (m, 8H), 0.9 (t, 6H); HPLC (40% CH3CN/H2O, C8): Rt=14.2 minutes.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl:5][C:6]1[N:11]=[C:10](Cl)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1>CCO>[Cl:5][C:6]1[N:11]=[C:10]([S:1][C:2]#[N:3])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1
Reactant: N#C[S-]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [K+]
Solvent: CCO
Product: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
(compound known, e.g. WO 2003/032994) Potassium thiocyanate (0.97 g, 10 mM) was added to a solution of 2,4-dichloro-5-nitropyrimidine (1.94 g 10, mM) in EtOH (40 mL) cooled to 0° C. via an ice bath. The solution was stirred at 0° C. for 30 min, then the bath was removed and the resulting suspension allowed to come to RT over 60 min, when water (100 mL) was added. The precipitate was collected via filtration, washed with ice cold water, dissolved with DCM, dried (MgSO4), filtered and evaporated to yield the titled compound (1.7 g). NMR CDCl3 1H δ 9.4 (s, 1H) ppm.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].O.C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: CCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCON=C(C(=O)OCC)c1csc(N)n1
Temperature: 40 °C
Yield: 62.8 %

Procedure:
Ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), thiourea (4.97 g.) and sodium acetate hydrate (8.89 g.) were dissolved in a mixture of water (40 ml.) and ethanol (50 ml.), and stirred at 40° C. for an hour. The reaction mixture was adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate under cooling and stirred at the same temperature for half an hour. The precipitating crystals were collected by filtration, washed with water and diisopropyl ether, and then dried to give crystalline ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10.55 g.), mp 142°-144° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH2:40]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 6.2 g (25.6 mmol, 1.01 eq) of hexadecanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), DI water (1×100 mL) and brine (1×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to an off-white solid. This solid was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield 13.1 g (22.5 mmol, 88.8%) of the product as an off-white solid with an HPLC purity of 94.0A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.76 Hz, 1H), 7.08 (d, J=2.32 Hz, 1H), 6.78 (dd, J=2.36, 8.72 Hz, 1H), 4.05 (t, J=6.8 Hz, 2H), 3.72 (m, 4H), 3.69 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.4 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 26H), 0.88 (t, J=6.68 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:25][N:26](C)CCN(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN1C(=O)CCC1.CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)#[N:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Br)cc3cccnc23)C1
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccnc23)C1
Temperature: 160 °C
Yield: 88.9 %

Procedure:
A solution of (S)-tert-butyl 3-((6-bromo-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate (1141 mg, 2.9 mmol), zinc cyanide (681 mg, 5.80 mmol) and N1,N1,N2,N2-tetramethylethane-1,2-diamine (87 μL, 0.580 mmol) in NMP was degassed with nitrogen for 5 minutes. Xantphos (168 mg, 0.290 mmol) and Pd2dba3 (266 mg, 0.290 mmol) were added and the mixture was heated in a microwave reactor at 160° C. for 10 minutes. The reaction mixture was subsequently diluted with EtOAc. The organic phase was washed with water (2×), dried, and concentrated in vacuo. The crude product was purified by preparative HPLC eluting with a gradient of 45-70% ACN in water (acid mode) to give the title compound as a yellow solid (175 mg, 17.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[C:17]1([C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:28]([C:24]4[S:25][CH:26]=[CH:27][C:23]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:29])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1sccc1-c1ccccc1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4sccc4-c4ccccc4)CC3C2)n1
Yield: 26.5 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 3-phenyl-thiophene-2-carboxylic acid (61.8 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (30.0 mg, 27.0%). MS (ESI) mass calcd. for C23H24N4OS, 404.54; m/z found 405.2 [M+H]+. 1H NMR (CDCl3): 7.45-7.41 (m, 2H), 7.39 (d, J=5.1, 1H), 7.34-7.27 (m, 2H), 7.18-7.14 (m, 1H), 7.13 (d, J=5.0, 1H), 6.28 (s, 1H), 3.88-3.66 (m, 2H), 3.61-3.49 (m, 2H), 3.30 (dd, J=11.5, 5.1, 1H), 3.19-3.04 (m, 2H), 2.92-2.78 (m, 1H), 2.75-2.61 (m, 2H), 2.37-2.22 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:21][C@H:19]1[NH:20][C:31](=[O:33])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:12][CH:13]=2)[C:18]1=[O:22]
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C)c(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-D-alaninamide (Intermediate 16, 118 mg) was dissolved in dry dichloromethane (18 mL). The reaction mixture was cooled down in an ice bath. Triethylamine 0.327 mL, 2.350 mmol) was added. Then a solution of triphosgene in dry dichloromethane (46.5 mg, 0.157 mmol) dissolved in 7 mL of dichloromethane was added. The reaction was stirred at 0° C. for 10 min under argon. A saturated aqueous solution of NaHCO3 was added (18 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×15 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue was purified by silica gel chromatography (Companion system, 12 g cartridge) eluting with a gradient cHex/EOAc from to 100/0 to 60/40 during 20 min and 60/40 during 30 min. This afforded the title compound (91 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=2[CH:13]=1.Cl.[CH3:15]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12][CH3:15])=[O:11])[C:6]=2[CH:13]=1
Reactant: CO
Reactant: O=C(O)c1coc2ccc(F)cc12
Agent: Cl
Product: COC(=O)c1coc2ccc(F)cc12
Reaction time: 24 h

Procedure:
A solution of 5-fluorobenzofuran-3-carboxylic acid (56 g) and saturated etheral solution of hydrochloric gas (300 mL) in methanol (600 mL) was stirred for 16 h at room temperature. Further etheral HCl was added (300 mL) followed by stirring for 24 h. Concentration in vacuo gave a dark crystalline material, methyl 5-fluorobenzofuran-3-carboxylate (58 g).