Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Fe](Cl)(Cl)Cl.C1C=CC=CC=1>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the presence of catalytic amounts of anhydrous iron (III) chloride, and under the appropriate conditions of temperature and pressure, benzoyl chloride and benzene react to form benzophenone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:18]S(O)(=O)=O>C(OCC)(OCC)OCC>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:1]=[CH:18][N:9]2[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:7][N:6]=1
Reactant: Nc1cnc(Cl)nc1NCc1ccccc1F
Reactant: CS(=O)(=O)O
Solvent: CCOC(OCC)OCC
Product: Fc1ccccc1Cn1cnc2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6.5 g (25.7 mmol) of 5-amino-2-chloro-4-[N-(2-fluorobenzyl)-amino]-pyrimidine are dissolved at room temperature in 65 ml of triethyl orthoformate. 30 mg of methanesulfonic acid are added to the solution and the reaction mixture is then stirred for 15 hours at room temperature. The reaction mixture is then concentrated by evaporation and the residue is chromatographed on silica gel with toluene/ethyl acetate (3:1) as eluant. The eluate is concentrated by evaporation and the residue obtained is recrystallised from dichloromethane/diethyl ether. In this manner 2-chloro-9-(2-fluorobenzyl)-9H-purine is obtained in the form of colourless crystals having a melting range of from 103° to 104°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:21])=[CH:23][CH:24]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:25])[C:6]=2[CH:26]=1
Reactant: Cc1c(C(CC(C)C)Nc2ccc(C(=O)O)cc2)oc2ccc(Cl)cc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2oc3ccc(Cl)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 86 %

Procedure:
To a mixture of 4-{[1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}benzoic acid (180 mg) synthesized above, β-alanine ethyl ester hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (111 mg), triethylamine (202 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg) and the mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (196 mg, 86%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].[CH:18]([NH2:21])([CH3:20])[CH3:19]>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][CH:18]([CH3:20])[CH3:19])[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: O=c1c2ccc(F)c(Br)c2nc(Cl)n1C1CC1
Reactant: CC(C)N
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nc2c(Br)c(F)ccc2c(=O)n1C1CC1
Yield: 92.1 %

Procedure:
A slurry of 8-bromo-2-chloro-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (721; 0.080 g, 0.252 mmol) in isopropylamine (Aldrich; 0.541 ml, 6.30 mmol) and 0.2 mL NMP was heated in a sealed tube in a biotage initiator microwave to 100° C. for 20 min. The reaction was partitioned between water and EtOAc. The organic layer was washed with water once, satd aq NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-3-cyclopropyl-7-fluoro-2-(isopropylamino)quinazolin-4(3H)-one (0.079 g, 0.232 mmol, 92% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (1H, dd, J=8.8, 6.5 Hz), 7.01 (1H, t, J=8.7 Hz), 6.85 (1H, d, J=7.6 Hz), 4.41 (1H, dq, J=13.6, 6.7 Hz), 2.64-2.79 (1H, m), 1.30 (6H, d, J=6.7 Hz), 1.19-1.27 (2H, m), 0.71-0.79 (2H, m). m/z (ESI, +ve ion) 340.0/342.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[CH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[C:16][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C#CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccccn1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CC#Cc2ccccn2)CCN(C)C1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole[(p-tolylhydrazine hydrochloride (600 mg, 3.7 mmol), propargyl bromide (80 wt % solution in toluene, 0.34 mL, 3.7 mmol), triethyl amine (1.5 mL, 11.3 mmol) and N-methyl-4-piperidone hydrochloride (316 mg, 2.1 mmol) were taken in ethanol (15 mL) to obtain 80 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with MeOH-DCM gradient) (150 mg, 0.6 mmol)], 2-bromopyridine (0.06 mL, 0.6 mmol), dichlorobis(triphenylphosphine) palladium (8 mg, 0.012 mmol), CuI (1 mg, 0.006 mmol), and triethylamine (0.01 mL 0.071 mmol) in acetonitrile (5 mL) was heated at 80° C. for 1.5 h to obtain 108 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL). 1H NMR (DMSO-d6, TFA salt) δ (ppm): 8.45-8.40 (d, 1H), 7.80-7.70 (t, 1H), 7.45-7.40 (m, 1H), 7.30-7.25 (t, 1H), 7.25 (s, 2H), 7.10-7.00 (d, 1H), 5.60 (s, 2H), 4.60-4.55 (d, 1H), 4.25-4.20 (d, 2H), 3.85-3.75 (d, 1H), 3.65-3.40 (m, 2H), 3.00 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([C:10]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])([CH:12]2[CH2:24][C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=4[C:14]=3[CH2:13]2)[F:11])[O:7][N:6]=1)=[O:4].[OH-].[Na+].[NH4+].[Cl-]>CO.C1COCC1.O>[C:28]1([S:25]([C:10]([CH:12]2[CH2:24][C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=4[C:14]=3[CH2:13]2)([F:11])[C:8]2[O:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:9]=2)(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reaction time: 2 h
Yield: 51.7 %

Procedure:
To a stirred solution of 600 mg (1.22 mmol) of (RS,SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carboxylic acid methyl ester in 5 mL of MeOH/THF 1:1, were added 980 mg (24.5 mmol, 20 eq) of NaOH in solution in 3 mL of water. After 2 hours at RT, aqueous NH4Cl was added until pH=7 was reached, the product was extracted with EtOAc, dried over Na2SO4, filtered and solvent evaporated. Column chromatography on silica gel with CH2Cl2/MeOH 8:2 yielded 300 mg (52%) of (RS,SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b ]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carboxylic acid as a white solid, MS: 430 (M-COOH).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH:42]1([C:45](O)=[O:46])[CH2:44][CH2:43]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>CC(N(C)C)=O>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:45]([CH:42]4[CH2:44][CH2:43]4)=[O:46])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(NC(=O)C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (20 mg, 0.037 mmol), cyclopropanecarboxylic acid (4.79 mg, 0.056 mmol), and HATU (21.18 mg, 0.056 mmol) was added DIEA (0.013 ml, 0.074 mmol) and DMA (1 ml). The vial was capped and the contents heated to 60° C. and stirred for 16 h. The reaction mixture was concentrated to afford crude (R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxamide which was taken forward without purification. MS ESI calc'd. For C38H35N6O2 [M+H]+ 607. found 607.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=O)[CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH3:22])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH3:22])[CH2:18][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C(=O)N1CCN(Cc2ccccc2)CC1)c1ccccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CN1CCN(Cc2ccccc2)CC1)c1ccccc1F
Temperature: 0 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
Lithium aluminium hydride (1M, 34 ml) was added dropwise over 15 min to a 0° C. solution of 4-benzyl-1-[2-(2-fluorophenyl)propanoyl]piperazine (5.54 g, 0.017 mol) in THF (150 ml). The reaction mixture was stirred at 0° C. for 10 min and at room temperature for 24 h, cooled to 0° C. and quenched with water (1.6 ml), 4N NaOH (1.6 ml) and water (4.5 ml). The solid was filtered off through celite and the filtrate evaporated. Chromatography on silica gel with dichloromethane-methanol (99:1) yielded 4-benzyl-1-[2-(2-fluorophenyl)propyl]piperazine (3.17 g, 60%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH:7]=1.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])C>[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:17]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([N:8]([C:17]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: CN(C)CCNc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [Ni]
Product: CCOC(=O)Nc1ccc(Cl)cc1N(CCN(C)C)C(=O)OCC
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of N-(5-Chloro-2-nitrophenyl)-N',N'-dimethylethylenediamine (1.02 g) in ethyl acetate (10 ml) was added Raney nickel and the reaction mixture was stirred under a hydrogen atmosphere at atmospheric pressure at 5° C. for 1 hour. The reaction mixture was then filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (15 ml), followed by dropwise addition of triethylamine (1.28 g) and ethyl chloroformate (1.14 g) in turn at 5° C. with stirring. The reaction mixture was further stirred at room temperature for 1 hour and diluted with water (10 ml). The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:chloroform:methanol=50:1) to give 1.05 g of N-(5-chloro-2-ethoxycarbonylaminophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:16]C(OC(C)(C)C)=O)[C:10]([C:13]([O-:15])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.F[C:27](F)(F)[C:28](O)=O>C(Cl)Cl>[NH2:16][C:9]1[C:10]([C:13]([O:15][CH2:27][CH3:28])=[O:14])=[N:11][CH:12]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cc2ccc(F)cc2)cnc1C(=O)[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N

Procedure:
A solution of 5-(4-fluorobenzyl)-3-[(tert-butoxy)carbonyl]amino-2-pyridinecarboxylate (29 g, 77 mmol) in CH2Cl2 (200 mL) and trifluoroacetic acid (60 mL) was stirred at rt overnight. The solvent was removed in vacuo and the crude material was dissolved in EtOAc and washed with NaHCO3 solution and brine. The organic layer was dried, concentrated and chromatographed on silica gel eluting with 20-60% EtOAc/hexanes to yield the product as a light yellow solid: 1H NMR (d6-DMSO) δ 7.76 (1H, d, J=1.7 Hz), 7.25 (2H, m), 7.15 (2H, t, J=9 Hz), 6.92 (1H, d,J=1.7 Hz), 6.62 (2H, br s), 4.23 (2H, q, J=7 Hz), 3.87 (2H, s), 1.26 (3H, t, J=7 Hz), AP+ MS: 275 (M+H+, 100); HRMS calcd for C15H15FN2O2+H+: 275.1196. Found: 275.1206.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.Cl.[NH:21]1[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]1.C(=O)([O-])O.[Na+]>C(O)CCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([N:21]3[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: OC[C@H]1CCNC1
Reactant: Clc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: OC[C@H]1CCN(c2ccc3ncc(-c4cc5ccccc5o4)n3n2)C1

Procedure:
150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine, 183.7 mg (1.34 mmol) (3S)-pyrrolidin-3-ylmethanol hydrochloride (1:1) and 186.9 mg (2.23 mmol) sodium hydrogencarbonate in 4.0 mL butan-1-ol were stirred 72 h at 150° C. The solvent was removed. The residue was purified by HPLC to yield 65 mg (35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:12]([OH:14])=[O:13])(=[O:17])[CH3:16]
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)cc(C(=O)O)n2C(C)=O
Temperature: 25 °C

Procedure:
The mixture of 20 g of 5-methoxyindole-2-carboxylic acid (J. Chem. Soc., 1970, 865) and 200 ml of acetic anhydride is refluxed for 2 hours and allowed to cool to room temperature. It is filtered, the filtrate evaporated and the residue is stirred in 300 ml of water. Excess sodium bicarbonate is added, the mixture stirred for 3 hours and then washed with 200 ml of diethyl ether. The aqueous layer is acidified to pH=1 with concentrated hydrochloric acid and filtration yields the 1-acetyl-5-methoxyindole-2-carboxylic acid melting at 173°-175°.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12]C(=O)C(C)(C)C)[CH3:2].[ClH:25]>>[ClH:25].[ClH:25].[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH:4]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[CH3:24])[NH:3][CH2:1][CH3:2]
Reactant: CCNC(Cc1ccccc1NC(=O)C(C)(C)C)c1sccc1C
Agent: Cl
Product: CCNC(Cc1ccccc1N)c1sccc1C

Procedure:
A solution of 9.2 g of N-[2-[2-(ethylamino)-2-(3-methyl-2-thienyl)ethyl]phenyl]-2,2-dimethylpropanamide in 160 ml of 6N hydrochloric acid was refluxed for 8 hrs. The solution was decanted over ice and basified with 50% sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Preparative HPLC (Water Associates Prep LC/System 500 A, silica gel, eluted with methanol, flow rate of 200 ml/min, Gow-Mac Model 80-800 uv detector). The appropriate fractions were collected and concentrated. The residue was dissolved in ether, filtered, and concentrated. The residue was dissolved in methanol, ethereal-hydrogen chloride was added, and the solution was diluted with anhydrous ether to afford 5.0 g of product, mp 202°-204° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[N:15]=2)=[CH:7][CH:6]=1.[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[N:15]=2)=[CH:7][CH:6]=1
Reactant: CC1CCCN1
Reactant: COC(=O)Cc1coc(-c2ccc(OCCCl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1coc(-c2ccc(OCCN3CCCC3C)cc2)n1
Reaction time: 45 h
Yield: 46.8 %

Procedure:
Methyl {2-[4-(2-chloroethoxy)phenyl]-1,3-oxazol-4-yl}acetate 151 (0.55 g, 1.86 mmol, 1 eq) is reacted with 2-methylpyrrolidine (0.28 ml, 2.79 mmol, 1.5 eq) in the presence of potassium carbonate (0.77 g, 5.58 mmol, 3 eq) and a catalytic quantity of sodium iodide in refluxing acetonitrile (20 ml). After 45 h, the solvent is evaporated, the residue is then taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 97:2.7:0.3) affords 0.3 g of methyl (2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)acetate i52.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][C:9]([O:11]CC)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+:15]>C1COCC1>[F:1][C:2]1[C:3]([CH2:8][C:9]([O-:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+:15]
Reactant: CCOC(=O)Cc1ncccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1ncccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A stirred solution of ethyl 2-(3-fluoropyridin-2-yl)acetate (1.90 g, 10.4 mmol) in THF (26 mL) was treated with 3 M aqueous NaOH (6.9 mL, 20.7 mmol) and stirred at room temperature overnight. The mixture was concentrated to remove the THF, and the residual aqueous solution was frozen and lyophilized to provide sodium 2-(3-fluoropyridin-2-yl)acetate as a white solid (assumed 100% yield), which was used without further purification. Mass spectrum m/z 156 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([C:21]([C:23]2[CH:24]=[CH:25][C:26]3[N:31]([CH2:32][CH:33]=[CH2:34])C(=O)O[C:28](=[O:36])[C:27]=3[CH:37]=2)=[O:22])[N:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2>CN(C=O)C>[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([C:21]([C:23]2[CH:37]=[C:27]3[C:26](=[CH:25][CH:24]=2)[N:31]([CH2:32][CH:33]=[CH2:34])[C:3]([CH3:5])=[C:2]([C:1]([O:7][CH2:8][CH3:9])=[O:6])[C:28]3=[O:36])=[O:22])[N:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2
Reactant: C=CCn1c(=O)oc(=O)c2cc(C(=O)c3c(C)c(OC)c4ccccn34)ccc21
Reactant: CCOC(=O)CC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1c(C)c(C(=O)OCC)c(=O)c2cc(C(=O)c3c(C)c(OC)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.49 ml (3.80 mmol) of ethyl acetoacetate diluted in 20 ml of anhydrous DMF is added, under an inert atmosphere at ambient temperature, to 0.66 g (1.52 mmol) of 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-1-prop-2-en-1-yl-2H-3,1-benzoxazine-2,4(1H)-dione in 30 ml of DMF. The reaction medium is stirred at ambient temperature overnight and then extracted with ethyl acetate. The organic phase obtained is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[CH2:28][C:29](O)=[O:30])[CH2:17][CH2:16]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:30]=[C:29]1[CH2:28][C@@H:23]2[C@H:22]([CH2:27][CH2:26][CH2:25][CH2:24]2)[N:21]1[CH:18]1[CH2:17][CH2:16][N:15]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:6][CH2:7]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3CC(=O)O)CC2)CC1
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: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1

Procedure:
A solution of 2-[(1R,2S)-2-[[1-[4-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-piperidyl]-4-piperidyl]amino]cyclohexyl]acetic acid, diisopropylethylamine (0.5 mL, 3.36 mmol) and HATU (0.7 g, 1.84 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction quenched with water and concentrated in vacuo. The residue was diluted in ethylacetate (100 mL) and washed with 1N NaOH (10 mL). The organic phase was separated and aqueous phase was extracted with ethylacetate (2×30 mL). The combined organic phases were dried and concentrated in vacuo to provide the title compound. MS (M+1): 420.38.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:10][Al](C)C.Cl>O1CCOCC1.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>[CH3:10][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C#N)ccn1
Yield: 57.6 %

Procedure:
A solution of 2-chloroisonicotinonitrile (2 g, 14.4 mmol), trimethylaluminum (7.94 ml, 15.9 mmol) and tetrakis(triphenylphosphine)palladium (0) (367 mg, 318 μmol) in dioxane (20.0 ml) was heated to reflux for 4 h. The reaction mixture was poured on 1N HCl and extracted two times with EtOAc. The aqueous layer was basified with 3N NaOH and extracted with EtOAc. The combined organic extracts were dried with Na2SO4 and evaporated. The remaining solid was purified by column chromatography (silica gel, dichloromethane/EtOAc 95:5) to afford the title compound (980 mg, 57%) as white solid. 1H NMR (CDCl3, 300 MHz): 2.64 (s, 3H), 7.34 (d, J=5.05 Hz 1H), 7.40 (s, 1H), 8.68 (d, J=5.05 Hz, 1H).
Reaction SMILES: C[C@H:2]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[N:5](C([C@@H](NS(C2C3NCC(C)CC=3C=CC=2)(=O)=O)CCCN=C(N)N)=O)[CH2:4][CH2:3]1.O.N[CH2:38]CCCCCCCCCCC(OC)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][C:8]([O:10][CH3:38])=[O:9]
Reactant: COC(=O)CCCCCCCCCCCN
Reactant: CC1CNc2c(cccc2S(=O)(=O)N[C@@H](CCCN=C(N)N)C(=O)N2CC[C@@H](C)C[C@@H]2C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN
Reaction time: 16 h
Yield: 169.2 %

Procedure:
To a solution of argatroban monohydrate (300 mg, 0.570 mmol) and methyl 12-aminododecanoate (compound YS-004-17) (132 mg, 0.576 mmol) in anhydrous DMF (15 mL) was added HBTU (258 mg, 0.680 mmol). Stirring was continued at room temperature for 16 hours. The precipitates formed during the reaction were filtered off and DMF was removed by vacuum distillation. The residue was purified by preparative TLC using solvents CH2Cl2 /MeOH/NH3 (90/10/1, v/v) to give the titled compound (140 mg) (Yield: 28%). 1HNMR (MeOH-4, 300 MHz).