Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:23]=[O:24])[C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1c(F)cccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N-(2-Bromo-6-fluorophenyl)pivalamide (7.0 g, 25.5 mmol) was dissolved in tetrahydrofuran (200 mL). The mixture was cooled to −78° C., and treated with butyllithium (2 M in cyclohexane, 31.0 mL, 62.0 mmol) dropwise. The reaction mixture was held at −78° C. for 30 minutes. A solution of N,N-dimethylformamide (10.0 mL, 129 mmol) in tetrahydrofuran (30 mL) was added to the reaction mixture dropwise. The reaction was held at −78° C. for 30 minutes and quenched by the addition of aqueous ammonium chloride. The mixture was allowed to warm to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Silica gel chromatography afforded the desired product as white solid in 80% yield. 1H NMR (300 MHz, CDCl3): δ 9.93 (d, J=1.83, 1H), 9.14 (bs, 1H), 7.56-7.50 (m, 1H), 7.42-7.25 (m, 2H), 1.34 (s, 9H). Mass spec.: 224.2 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:56]=[CH:55][CH:54]=[CH:53][C:49]=1[C:50](Cl)=[O:51]>C(Cl)Cl>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:50](=[O:51])[C:49]2[CH:53]=[CH:54][CH:55]=[CH:56][C:48]=2[F:47])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)c5ccccc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.3 %

Procedure:
To a solution of aniline 46 (300 mg, 0.569 mmol) in DCM (10 mL) at 0° C. was added DIPEA (0.199 mL, 1.137 mmol) and 2-fluorobenzoyl chloride (135 mg, 0.853 mmol) and the suspension was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was collected, dried and concentrated. The residue was purified using Biotage (eluent EtOAc, 25 g Silicycle HR column) to provide the title compound 356 (400 mg, 0.616 mmol, quantitative yield) as a white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:15]=1[Cl:1]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-chlorosuccinimide (1 eq, 7.45 g, 55.8 mmol) was added to a solution of ethyl 4-aminophenylacetate (10 g, 55.8 mmol) in chloroform (200 mls). The reaction mixture was stirred at room temperature, under argon, for 15 minutes. The reaction mixture was washed with water (250 mls) and the organic layer collected using a hydrophobic frit. This was evaporated to dryness to give a dark brown oil, 9.8 g.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:21][NH:20][CH2:19]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(#N)C>[CH2:1]([C:3]1[C:8]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[C:12]([CH3:14])([CH3:15])[O:13]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:21][N:20]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:19]1)[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CC(c2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)C1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of 3-[2-ethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-azetidine (D131) (295 mg, 0.735 mmol) in Acetonitrile (10 mL) was added potassium carbonate (305 mg, 2.206 mmol) and ethyl 4-bromobutanoate (0.158 mL, 1.103 mmol). The reaction solution was heated to 60° C. overnight. The solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with water, dried and concentrated to afford ethyl 4-{3-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-azetidinyl}butanoate (D132) (295 mg) as an oil. MS (ES): C23H36BNO4 requires 401.3. found 402.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7]C)=[O:6].[CH:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH:12]([C:15]1[N:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([OH:7])=[O:6])[CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ncc[nH]1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)c1nccn1-c1cc(C(=O)O)ccn1
Temperature: 120 °C
Yield: 54.9 %

Procedure:
A mixture of methyl 2-bromoisonicotinate (2.00 g, 9.26 mmol), 2-isopropyl-1H-imidazole (1.12 g, 10.2 mmol), cesium carbonate (6.03 g, 18.5 mmol) and copper(1) Iodide (176 mg, 926 umol) in DMSO was heated to 120° C. for eighteen hours, under nitrogen. The crude material was filtered, purified by preparative HPLC (10-90% CH3CN in water). The pure fractions were collected and concentrated to give 2-(2-isopropyl-1H-imidazol-1-yl)isonicotinic acid as a white sticky solid (1.176 g, 55% yield). MS 232 (MH+).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]#[N:8])=[N:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[S:6][C:5]([C:7]#[N:8])=[N:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: N#Cc1nnc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C#N)s2)CC1
Yield: 91.1 %

Procedure:
A mixture of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (0.5 g, 3.44 mmol) (prepared by a procedure similar to that described in U.S. Pat. No. 5,736,545), and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.69 g, 3.44 mmol) and diisopropylethylamine (0.72 ml, 4.13 mmol) in acetonitrile (10 ml) was stirred at 130° C. for 30 min., under microwave irradiation. After this period, the solvent was evaporated in vacuo. The crude product was dissolved in dichloromethane and extracted with a saturated solution of ammonium chloride. The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by short open column chromatography (silica gel; 3-5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo to yield D5 (0.97 g, 63%) as a white solid. C13H19N5O2S requires 309. Found 308 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:7]([OH:9])=[O:8])([CH3:3])=[CH2:2].[H][H]>C(O)C.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(C)C)c2)nc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 3-isopropenyl-5-(5-methylpyridin-2-yl)benzoic acid (150 mg, 0.592 mmol) in ethanol (11.8 mL) was added 10% palladium on carbon (50.0 mg, 0.047 mmol) and the mixture was placed under 1 atm of hydrogen. After 1 h, filtration and concentration gave the crude title compound (150 mg). MS 256.2 (M+1).
Reaction SMILES: Br.[NH:2]1[C:6]([C:7]2[C:15](=N)[N:14]3[C:10]([S:11][C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=43)=[N:9][CH:8]=2)=[N:5][N:4]=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].N1C=CC=CC=1>O>[NH:2]1[C:6]([C:7]2[C:15](=[S:22])[N:14]3[C:10]([S:11][C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=43)=[N:9][CH:8]=2)=[N:5][N:4]=[N:3]1
Reactant: N=c1c(-c2nnn[nH]2)cnc2sc3ccccc3n12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Br
Solvent: c1ccncc1
Solvent: O
Product: S=c1c(-c2nnn[nH]2)cnc2sc3ccccc3n12

Procedure:
- The product of Example 24, 0.02 mole, and 12.0 g. (0.054 mole) of P2S5 in 125 ml. of pyridine is heated at reflux for 5 hrs. and then poured into 1 l. of ice and water mixture. The product is collected by filtration, the solid dissolved in dilute NaOH, treated with decolorizing carbon, filtered and the filtrate acidified whereupon the purified product precipitated and was collected on a filter.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([CH:8]([CH2:13][C:14]([O:16]C)=[O:15])[C:9](OC)=[O:10])(=O)[CH3:6].[Na]>CO>[OH:10][C:9]1[C:8]([CH2:13][C:14]([OH:16])=[O:15])=[C:5]([CH3:6])[N:4]=[C:2]([SH:3])[N:1]=1
Reactant: NC(N)=S
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: [Na]
Solvent: CO
Product: Cc1nc(S)nc(O)c1CC(=O)O
Yield: 94.9 %

Procedure:
Thiourea (80 g, 1.05 mol) and dimethyl acetylsuccinate (188 g, 1.0 mol) are added at room temperature to a solution of sodium (46 g, 2.0 mol) in methanol (800 ml). The reaction mixture is refluxed for 14 hours. The crystalline precipitate is filtered and added with stirring to a concentrated aqueous solution of hydrochloric acid (250 ml). The resulting colorless crystalline precipitate is filtered, washed with methanol and dried at high vacuum to give 4-hydroxy-2-mercapto-6-methyl-5-pyrimidinyl acetic acid (190 g, 95%). 1H-NMR (DMSO):12.4 (s, 1H); 12.3 (s, 1H); 3.4 (s, 2H); 2.1 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[NH:9][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[C:17]([F:23])[CH:16]=1>O1CCCC1>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=1[C:6]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][C:17]=1[F:23])=[O:11]
Reactant: NCc1ccc(Br)cc1F
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Yield: 79.9 %

Procedure:
A mixture of 7-chloro-2H-3,1-benzoxazine-2,4(1H)dione (18.4 g) and 4-bromo-2-fluorobenzylamine (26 g) in tetrahydrofuran (200 ml) was refluxed for 15 minutes. After cooling, tetrahydrofuran was evaporated to give a residue. Recrystallization from isopropyl ether gave 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide (26.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.C([Li])CCC.[I:17]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([I:17])[S:8][C:7]=2[CH:11]=1
Reactant: II
Reactant: COc1ccc2ccsc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(I)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
To a solution of 6-methoxybenzo[b]thiophene (5.00 g, 30.49 mmol) in 200 mL of anhydrous THF at -78° C., was added n-butyllithium (20.0 mL, 32.01 mmol, 1.6M solution in hexanes). After stirring for 15 minutes, a solution of I2 (8.10 g, 32.01 mmol) in 25 mL of anhydrous THF was introduced dropwise via canula. The resulting mixture was allowed to gradually warm to ambient temperature. The reaction was quenched by distributing between ethyl acetate/brine (150 mL each). The layers were separated and the organic layer was dried over sodium sulfate. Concentration in vacuo produced a tan solid that was recrystallized from hexanes to provide 6.70 g (75%) of 6-methoxy-2-iodobenzo [b]thiophene. mp 75°-77° C. 1H NMR (CDCl3) d 7.59 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=2.0 Hz, 1H), 6.92 (dd, J=8.6, 2.0 Hz, 1H) , 3.86 (s, 3H) . FD mass spec: 290. Anal. Calcd. for C9H7OSI: C, 37.26; H, 2.43. Found: C, 37.55; H, 2.43.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: COC(=O)C1CCC(c2ccccc2)C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1CCC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 65% nitric acid (0.95 mL) and 95% sulphuric acid (1.2 mL) in carbon tetrachloride (2.5 mL) was added dropwise to a solution of methyl 3-phenylcyclopentanecarboxylate (Journal of Organic Chemistry, 1988, 53(17), 4021) (1 g, 4.9 mmol) and the mixture was stirred at 5-10° C. for 2 h. Ice/water (30 mL) was added and the mixture was extracted with DCM (2×50 mL). The extracts were combined, washed with water and dried. The residue was adsorbed onto silica and purified by chromatography eluting with 0-30% EtOAc in hexane to give the title compound (782 mg, 64%) as an oil; 1H NMR δ3.90 (3H, s), 7.94-7.97 (2H, m), 8.03-8.06 (2H, m), 8.09-8.12 (2H, m), 8.33-8.36 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C@@H:13]2[CH2:15][O:14]2)=[CH:5][C:4]=1[N:16]=[CH:17][N:18]([CH3:20])[CH3:19])#[N:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl.C(O)C>[C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:5][C:4]=1[N:16]=[CH:17][N:18]([CH3:20])[CH3:19])#[N:2]
Reactant: C1CCNCC1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@@H]1CO1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@@H](O)CN1CCCCC1
Yield: 85.7 %

Procedure:
N′-(2-cyano-5-(2S)-oxiranylmethoxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (850 mg, 3.09 mmol) in chloroform (6 ml) and ethanol (12 ml) was irradiated with piperidine (0.46 ml, 4.6 mmol) in a microwave oven at reflux for 10 minutes. The solvent was evaporated and the residue was purified by silica gel chromatography, eluant CH2Cl2/MeOH 90/10 to give title compound (954 mg, 86%).
Reaction SMILES: [C:1]([O:20]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26].CC(C)([O-])C.[K+]>>[CH3:27][C:24]([CH3:28])([CH2:25][OH:26])[CH2:23][NH:22][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(CN)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCCCC(=O)NCC(C)(C)CO
Temperature: 190 °C

Procedure:
In a 500 ml, three-neck, round-bottom flask equipped with a thermometer, stirrer and a Stark and Dean trap with condenser were placed 119.4 g of methyl stearate, 41 g of 3-amino-2,2-dimethylpropanol and 3 g of potassium tert-butoxide. The mixture was heated to 190° C., and the methanol distilled off. The reaction mixture was dissolved in hot isopropanol and filtered. On cooling, the product crystallized, and after filtration and drying it melted at 44° C. IR showed an ester carbonyl. The pure product was obtained by washing with hot hexane. The pure product melted at 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[C:14](O)(=O)[CH2:15][CH2:16][CH3:17].Cl>[OH-].[NH4+]>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:14]([CH2:15][CH2:16][CH3:17])=[N:1][C:2]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: CCCC(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCCc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1
Yield: 40.5 %

Procedure:
A mixture of 9.0 g of 2-amino-4-chloro-5-sulfamyl aniline, 14.1 g of butyric acid, and 40.3 ml of a 15% hydrochloric acid solution was refluxed for 6 hours and then concentrated in vacuo to a solid. The solid was dissolved in hot methanol, treated with charcoal, boiled ten minutes, and filtered. Concentration in vacuo provided a solid which was then added portionwise to 200 ml of concentrated ammonium hydroxide. The free base was then recrystallized from acetonitrile to yield 4.5 g of pink crystals, m.p. 230°-234°.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(N(C)C)=O.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1cnnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cnn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
3-Chloro-5-trifluoromethyl-pyridazine (200 mg) was added to piperazine-1-carboxylic acid tert-butyl ester (231 mg) in dimethylacetamide (3 mL), and the reaction mixture was stirred at 100° C. for 3 hours. After such time, the reaction mixture was allowed to cool down to room temperature and diluted with ethyl acetate. The solid was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and then purified by column chromatography (SiO2, Heptane/EtOAc) to yield the title compound as a white solid (364 mg). MS (m/e): 333.4 (M+H+, 100%)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.Br.NC(N)=[S:16]>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10][SH:16])=[CH:4][CH:3]=1
Reactant: CC(CCO)c1ccc(I)cc1
Reactant: NC(N)=S
Agent: Br
Solvent: O
Product: CC(CCS)c1ccc(I)cc1
Yield: 41 %

Procedure:
70 g of 3-(p-iodophenyl) butanol was combined in solution with 138 g of hydrobromic acid (48%) and 20 g thiourea in 100 ml of water and the thiol product vacuum distilled at 126° and 0.18 mm Hg. A 41% yield of 3-(p-Iodophenyl) butane thiol was confirmed having a refractive index of n25D = 1.6071 and nmr, ir and gc readings commensurate with the structure of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[N:28]([C@H:29]2[CH2:34][CH2:33][C@H:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]2)[N:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[N:27][N:28]([C@H:29]4[CH2:30][CH2:31][C@H:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34]4)[C:24]=3[CH3:23])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c2C)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (60.0 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=539.16/541.16 (100/50) [MH+]. HPLC: tR=3.98 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])[CH3:2].[CH3:19][N:20]1C(=O)CCC1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]#[N:20])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1nc(I)c2cc(Br)ccc2c1O
Solvent: ClCCl
Product: CCOC(=O)c1nc(C#N)c2cc(Br)ccc2c1O
Temperature: 120 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
7-Bromo-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid ethyl ester (1.0 g, 2.37 mmol) was dissolved in anhydrous NMP and cuprous cyanide was added (255 mg, 2.844 mmol) was added as a solid in one portion. The solution was heated to 120° C. in an oil bath. Upon completion, the reaction was cooled, diluted with 15 volumes of dichloromethane and stirred overnight. The following day the solution was washed with 1M hydrochloric acid, water, then brine and dried over sodium sulfate. The crude material was purified by medium pressure liquid chromatography (20 to 75% ethyl acetate in hexanes) to give the desired material in 85% yield as tan solid. 1H NMR (200 MHz, CDCl3): δ ppm=12.48 (s, 1H), 8.46 (s, 1H), 8.32 (d, 1H), 7.94 (d, 1H), 4.59 (q, 2H), 1.53 (t, 3H.)
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][OH:17])=O)C1C=CC=CC=1.C(O)C.CCO.[H][H]>C(N(CC)CC)C.CCN(CC)CC.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][OH:17]
Reactant: [H][H]
Reactant: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCNC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCN)OCc1ccccc1
Reaction time: 2 h

Procedure:
In a three-neck flask, the catalyst (150 mg of 20% palladium/carbon) was added to the solution of (2R)-5-(benzyloxycarbonylamino)-2-[(R)-3-benzyloxytetradecanoylamino]pentan-1-ol (3.0 g; 5.27 mmol) in a mixture of triethylamine Et3N (6 ml)/HPLC-grade ethanol EtOH (300 ml). Air was discharged under vacuum then the flask was loaded with hydrogen. The reaction mixture was hydrogenated at room temperature for 2 hours then the catalyst was filtered off and the filtrate was concentrated to provide the desired product as a homogenous white solid. Rf=0.2, 5/1 0/0.5 CH2Cl2-MeOH-Et3N, m.p.=47-48° C.