Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)C(=O)O1>O(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[F:21][C:18]([F:19])([F:20])[O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:5][C:6]2=[O:8]
Reactant: CC1(C)OC(=O)C(=CNc2ccc(OC(F)(F)F)cc2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: O=c1cc[nH]c2ccc(OC(F)(F)F)cc12
Temperature: 250 °C
Reaction time: 0.08 h

Procedure:
In a 50 mL round bottom flask with a reflux condenser attached was dissolved 2,2-dimethyl-5-((4-(trifluoromethoxy)phenylamino)methylene)-1,3-dioxane-4,6-dione (1.00 g, 3.02 mmol) in Ph2O (8.63 mL, 0.35 M). The mixture was heated to 250° C. in a heating mantle. At about 180° C., the reaction turned from a light yellow and homogeneous to an orange, then to a dark brown color and began to bubble, slowly at first and then more violently. Internal temperature of reaction went up to 230° C., although heating ceased at 180° C. Heating at 250° C. while stirring was continued for five minutes, and the reaction was cooled to RT, diluted with hexane, and the precipitate was filtered to yield 6-(trifluoromethoxy)quinolin-4(1H)-one as a crude brown solid. MS [M+H]=230.1; Calc'd 229.2 for C10H6F3NO2.
Reaction SMILES: [C:1]([C:6]1[C:17]([Cl:18])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Mn]([O-])(=O)(=O)=[O:20].[K+]>>[C:1]([C:6]1[C:17]([Cl:18])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([C:13]([OH:20])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCC(=O)c1cc2nc(CO)n(C)c2cc1Cl
Agent: [K+]
Product: CCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1Cl

Procedure:
In a manner analogous to that described in Example 12, 2.7 g of 5-butyryl-6-chloro-1-methyl-benzimidazole-2-methanol are oxidised with 2.5 g of potassium permanganate to give 5-butyryl-6-chloro-1-methyl-benzimidazole-2-carboxylic acid with a melting point of 90° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2.C(OC([NH:27][CH2:28][CH2:29][CH:30]=O)=O)C1C=CC=CC=1.C([BH3-])#N.[Na+].O.N.C([O-])=O.[NH4+]>[Pd].CO.C(O)(=O)C>[NH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)c1cc2cccc(N)c2n1C
Agent: [Pd]
Agent: N
Agent: O=C[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cc2cccc(NCCCN)c2n1C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 20.6 %

Procedure:
A mixture of 4.00 g (18.3 mmol) of ethyl 7-amino-1-methyl-2-indolecarboxylate, 7.60 g (37.6 mmol) of 3-(benzyloxycarbonylamino)propion aldehyde, 2.43 g (38.6 mmol) of sodium cyanoborohydride, 2.1 ml of acetic acid, 5.0 g of molecular sieves 3A and 200 ml of methanol was stirred at room temperature for 4.5 hours. After 28% ammonia water was added to the reaction solution to render the system alkaline, the reaction mixture was extracted three times with ethyl acetate. The combined extracts were then washed with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was suspended in 100 ml of ethanol. After 6.40 g (101 mmol) of ammonium formate and 0.91 g of 10% palladium/carbon were added to the suspension, the mixture was heated to reflux for 8 hours. Insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The thus obtained residue was isolated and purified by silica gel column chromatography to give 1.04 g (24.6%) of ethyl 7-[(3-aminopropyl)amino]-1-methyl-2-indolecarboxylate.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([NH:36][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(N)n3)ccc2n1CC1CCOCC1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(NC(=O)C4CCC4)n3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Cyclobutanecarbonyl chloride (30 mg, 30 uL, 0.26 mmol) was added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazol-3-amine (37 mg, 0.087 mmol) (see Example 21 for preparation) and DIPEA (34 mg, 46 uL, 0.26 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 14.3 mg (33%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.56 (m, 4 H), 1.59 (s, 9 H), 1.76-1.88 (m, 1 H), 1.91-2.01 (m, 1 H), 2.06-2.18 (m, 2 H), 2.17-2.27 (m, 2 H), 2.26-2.37 (m, 1 H), 3.10-3.24 (m, 1 H), 3.25-3.35 (m, 2 H), 3.84-3.95 (m, 2 H), 4.41 (d, J=7.62 Hz, 2 H), 6.87 (d, J=2.93 Hz, 1 H), 7.88 (d, J=8.9 Hz, 1 H), 7.92 (dd, J=8.8, 1.5 Hz, 1 H), 8.18 (d, J=2.93 Hz, 1 H), 8.25 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=499.8; Anal. Calcd for C25H33N5O4S+0.80 TFA+0.20 EtOAc+0.10H2O (612.68): C, 54.11; H, 5.86; N, 11.43. Found: C, 54.12; H, 5.92; N, 11.34.
Reaction SMILES: [ClH:1].C[C:3]1C=C2[C:6]([NH:7]C=C2CCN)=[C:5](Br)[CH:4]=1.Cl.[CH3:17][C:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[ClH:1].[CH3:17][C:18]([C:21]1[CH:26]=[C:25]2[C:24]([NH:27][CH:3]=[C:4]2[CH2:5][CH2:6][NH2:7])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(NN)cc1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: CC(C)(C)c1ccc2[nH]cc(CCN)c2c1

Procedure:
5-(1,1-dimethylethyl)-tryptamine hydrochloride was prepared (2.95 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4-(1,1-dimethylethyl)-phenyl hydrazine hydrochloride (6.00 g) as starting material.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]=1C(O)=O)[CH3:2].[H-].[Na+].[CH3:18][C@@H:19]1[CH2:21][O:20]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([CH2:18][C@H:19]([OH:20])[CH3:21])[CH:4]=1)[CH3:2]
Reactant: CCc1c(C(=O)O)[nH]c2ccc(F)cc12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cn(C[C@@H](C)O)c2ccc(F)cc12
Reaction time: 2 h
Yield: 62 %

Procedure:
A suspension of 1.21 g of 3-ethyl-5-fluoroindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 2 hours and, after cooling to 0°, diluted with 29 ml of tetrahydrofuran. 218 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.61 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 90 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:2) and subsequently with toluene-ethyl acetate (9:1). 0.8 g (62%) of (R)-1-(3-ethyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as pale brown crystals with m.p. 65°-67°.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([C:22]([NH:35][CH:36]2[C:56](=[O:57])[N:38]3[CH:39]([C:44](=[N:46][CH2:47][C:48]4[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=4)[NH2:45])[C:40]([CH3:43])([CH3:42])[S:41][C@H:37]23)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:58](O)(=[O:63])[CH2:59][C:60](O)=[O:61]>CN(C)C=O.C(Cl)Cl>[C:29]1([C:22]([NH:35][CH:36]2[C:56](=[O:57])[N:38]3[CH:39]([C:44]4[N:46]([CH2:47][C:48]5[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=5)[C:58](=[O:63])[CH2:59][C:60](=[O:61])[N:45]=4)[C:40]([CH3:43])([CH3:42])[S:41][C@H:37]23)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(CN=C(N)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Reactant: O=C(O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC(=O)N=C2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 21.44 g. (104 mmoles) of N,N'-dicyclohexylcarbodiimide in 122 ml. of methylene chloride and 15 ml. dimethylformamide at -5° C., a solution of 29.9 g. (52 mmoles) of 6-(triphenylmethylamino)-2,2-dimethyl-3-[N'-(4-methoxybenzyl)amidino]penam and 5.41 g. (52 mmoles) of malonic acid in 122 ml. methylene chloride and 15 ml. dimethylformamide is added dropwise over 2 hours. The mixture is then stirred for 24 hours at 25° C. The N,N'-dicyclohexylurea precipitate (18.6 g., 79.8% of theory) is filtered off, and the filtrate washed with six 150 ml. portions of water. It is dried over anhydrous sodium sulfate and then rotoevaporated to yield the title compound in crude form as an orange foam (32.6 g.). The crude product is divided into two equal portions for silica gel chromatography (ethyl acetate elution) affording a total of 10.61 g. (31.6%) of the purified title compound. 1H--NHR (CDCl3) ppm (δ) 1.01 (3H, s, 2--CH3); 1.44 (3H, s, 2--CH3); 3.80 (3H, s, --OCH3); 4.31-4.73 (3H, m; 3-, 5- and 6--H); 5.25 (2H, s, --CH2 --); 4H, AB, Ha within a 7.18-7.68 multiplet, Hb centered at 6.91, J= 8 Hz, CH3O--C6H4 --); 7.18-7.68 (15H, m, C6H5 --).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9]C(=O)C)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1ccc(Cl)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(Cl)ccc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
A mixture of acetic acid 6-chloro-2-methyl-pyridin-3-yl ester (316 mg, 1.7 mmol) and 15% aqueous sodium hydroxide (2.5 mL) was stirred at 0° C. for 15 min and then at room temperature for 1 h. 1 M HCl (12 mL) was added and the mixture was extracted 4 times with ethyl acetate. The ethyl acetate was evaporated to give 6-chloro-2-methyl-pyridin-3-ol (235 mg, 96%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H), 7.09 (d, 1H, J=8.4 Hz), 7.14 (d, 1H, J=8.4 Hz), 10.08 (br s, 1H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]([F:23])[CH3:22].C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>C1COCC1.Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[C:16]([F:20])[C:15]=1[CH:21]([F:23])[CH3:22]
Reactant: CC(F)c1c(F)cccc1Cl
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
A 2.5M solution of n-butyllithium (13 mL, 33 mmol) was added to a stirred solution of diisopropylamine (5.0 mL, 35 mmol) in THF (50 mL) at −78° C. The resulting colorless solution was stirred at −78° C. for 20 min, warmed to 0° C. for 20 min, and then cooled back to −78° C. for 20 min. A solution of 1-chloro-3-fluoro-2-(1-fluoroethyl)benzene (4.8 g, 27 mmol, 1.0 equiv) in THF (20 mL) at −78° C. was transferred to the base solution via cannula. The resulting dark brown solution was stirred at −78° C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.3 mL, 41 mmol, 1.5 equiv) was added and the brown solution was slowly warmed to 23° C. over 20 h. The reaction mixture was diluted with 0.1M hydrochloric acid (300 mL) and extracted with dichloromethane thrice. The combined organic extracts were dried, filtered and concentrated by rotary evaporation to afford the title compound as a brown oil that solidified into a semi-solid upon standing (7.7 g, 94% yield). 1H NMR (300 MHz, CDCl3) δ 7.62 (m, 1H), 7.17 (m, 1H), 6.13 (dq, 1H, J=6, 46 Hz), 1.75 (ddd, 3H, J=1, 7, 23 Hz), 1.36 (s, 12H).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[F:9][C:10]1([F:39])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[C@@H:12]([C:23](=[O:38])[NH:24][C:25]2([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=3)[CH2:27][CH2:26]2)[CH2:11]1>>[F:39][C:10]1([F:9])[CH2:15][CH2:14][NH:13][C@@H:12]([C:23]([NH:24][C:25]2([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:38])[CH2:11]1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)(F)CCN3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)(F)CCN3)CC2)cc1
Yield: 89.6 %

Procedure:
The title compound (D98) (47 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (R)-tert-butyl 4,4-difluoro-2-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1-carboxylate (D67) (68 mg).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][N:5]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[I:6].[OH-].[Li+].S([O-])(O)(=O)=O.[K+].Cl>C(Cl)Cl.C(O)(=O)C.O1CCCC1>[I:6][N:5]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[CH2:4][C:3]([OH:13])=[O:2]
Reactant: C#CCOC(=O)N(I)CC(=O)OC
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#CCOC(=O)N(I)CC(=O)O
Temperature: 0 °C

Procedure:
N-Iodopropargyloxycarbonyl glycine methyl ester (Compound 2, 8.03 g., 27.03 mmole) was dissolved in 100 ml. of tetrahydrofuran, cooled to 0° C. with an ice bath and treated during 15 minutes with 30.5 ml. of 1M aqueous lithium hydroxide. The reaction mixture was stirred at 0° C. for 3/4 hr. or until the starting material was no longer present. The reaction progress was monitored by thin layer chromatography (silica gel, methylene chloride/acetic acid 90:10). After the reaction was complete, the aqueous solution was acidified (pH=2) with 10% aqueous potassium hydrogen sulfate (100 ml) and 3N aqueous hydrogen chloride (10 ml.). This mixture was extracted several times with diethyl ether. The ether layers were combined and washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-iodopropargyloxycarbonyl glycine (Compound 1) as a pale amber oil, which crystallized upon standing (6.63 g., 86.7% yield after drying in vacuo over P2O5). m.p. 108° -110° C. 1H-NMR (200 MHz., DMSOd6) δppm =3.67., d, 2H (--NH--CH2 --), 4.76, s, 2H (C--CH2 --O), 7.66, t, 1H (NH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:22])=[C:16]3[C:21]=2[CH2:20][NH:19][CH2:18][CH2:17]3)=[C:8]([O:23][CH2:24][CH3:25])[CH:7]=1)[CH3:2].C(N(C(C)C)C(C)C)C.[F:36][C:37]1[CH:54]=[CH:53][C:40]([CH2:41][O:42][C:43](=O)[O:44]N2C(=O)CCC2=O)=[CH:39][CH:38]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])=[CH:7][C:8]=4[O:23][CH2:24][CH3:25])[CH:13]=[CH:14][C:15]=3[F:22])[CH2:20]2)=[O:44])=[CH:53][CH:54]=1
Reactant: O=C(OCc1ccc(F)cc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CNCC3)c(OCC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CN(C(=O)OCc2ccc(F)cc2)CC3)c(OCC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3-ethoxy-4-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (1.49 g, 4.2 mmol, 1.00 eq.) and N-ethyldiisopropylamine (3.56 mL, 20.8 mmol, 5.00 eq.) in DCM (50 mL), carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-fluoro-benzyl ester (1.17 g, 4.4 mmol, 1.05 eq.) was added. The mixture was stirred at r.t. for 18 hours. The solution was diluted with sat. aq. NaHCO3 soln. (100 mL). The layers were separated. The aq. phase was extracted with DCM (2×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 100 fractions of 45 mL, Heptane 100% to Heptane+40% AcOEt) to yield the title compound as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:15])[CH:7]([P:9]([O:13]C)([O:11]C)=[O:10])[OH:8])CCC>Cl>[P:9]([CH:7]([OH:8])[C:6]([OH:15])=[O:5])([OH:13])([OH:11])=[O:10]
Reactant: CCCCOC(=O)C(O)P(=O)(OC)OC
Agent: Cl
Product: O=C(O)C(O)P(=O)(O)O
Yield: 85 %

Procedure:
27 g of dimethoxyphosphinyl-hydroxy-acetic acid butyl ester and 200 ml of 5 N hydrochloric acid are boiled under reflux for 15 hours. The water is distilled off, the product is freed from residual water by azeotropic distillation with toluene and 15.0 g of phosphono-hydroxy-acetic acid are obtained (yield: 85%). 1H-NMR (D2O): δ=4.56 ppm (1H, d, J=18 Hz, P--CH)
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([O:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2nc(NC(=O)CO)sc2c1
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)COC(=O)c3ccccc3)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Hydroxyacetylamino)-6-methoxybenzothiazole (1.2 g) prepared in Example 3 is dissolved in pyridine (50 ml) and thereto is added dropwise benzoyl chloride (0.6 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off, washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (1.3 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11]C(=O)C)=[N:9][C:8]([O:15][CH2:16][CH2:17][F:18])=[CH:7][N:6]=1)=[O:4].C[O-].[Na+].[NH4+].[Cl-]>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([O:15][CH2:16][CH2:17][F:18])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(OCCF)nc1NC(C)=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ncc(OCCF)nc1N
Reaction time: 1 h
Yield: 85 %

Procedure:
To a mixture of 3-acetylamino-5-(2-fluoro-ethoxy)-pyrazine-2-carboxylic acid methyl ester (330 mg, 0.962 mmol) in dry MeOH (12 ml) was added sodium methoxide (52.0 mg, 0.962 mmol) at 0° C. The resulting suspension was stirred at it for 1 h. Saturated aq. NH4Cl, was added and then mixture was extracted with EtOAc. The combined organic layers were dried with Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel (DCM to DCM/EtOAc 9:1) to provide the title compound as white solid (176 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>C(#N)C>[CH2:21]([O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([Cl:11])[CH:4]=1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(Cl)c([N+](=O)[O-])cc1Cl
Yield: 93.5 %

Procedure:
The product of step (a) (59.3 g, 285 mmol), 550 ml acetonitrile, 43 g (314 mmol) of potassium carbonate and 27.2 ml (314 mmol) of allyl bromide were combined and heated to reflux, and then the reaction was evaporated under reduced pressure. The mixture was extracted with diethyl ether, washed with water, and separated. The organics were dried over magnesium sulfate and stripped to yield 66.1 g of 4-allyloxy-2,5-dichloronitrobenzene product.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4].F[C:23]1[N:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].C(N(CC)CC)C>C(#N)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:23]2[C:24]([C:25]#[N:26])=[CH:27][CH:28]=[CH:29][N:30]=2)[CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCNC1
Reactant: N#Cc1cccnc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(c2ncccc2C#N)C1
Temperature: 60 °C
Yield: 75.8 %

Procedure:
To a 20-mL scintillation vial were added the product from Example 104B (54.2 mg, 0.175 mmol), the 2-fluoronicotin-onitrile (Aldrich, 32.1 mg, 0.263 mmol), and anhydrous acetonitrile (2 mL). Neat triethylamine (53.1 mg, 0.525 mmol) was added. The reaction mixture was heated to 60° C. in a heated shaker block and mixed for 24 hours. After cooling to room temperature, the volatiles were removed by rotary evaporator. The product was purified by flash chromatography (silica gel: 20-65% ethyl acetate in hexanes) to give 54.6 mg (76%) of the title compound. 1H NMR (DMSO-d6) δ 0.88 (t, J=7.3 Hz, 3H), 1.21-1.34 (m, 3H), 1.52-1.62 (m, 1H), 1.57 (s, 9H), 2.20-2.27 (m, 2H), 2.59-2.64 (m, 2H), 3.35-3.43 (m, 1H), 3.69-3.78 (m, 2H), 3.88-3.95 (m, 1H), 4.04-4.09 (m, 1H), 6.69 (dd, J=7.5, 4.8 Hz, 1H), 7.93 (dd, J=7.9, 2.0 Hz, 1H), 8.31 (dd, J=4.8, 2.0 Hz, 1H), 8.57 (s, 1H). MS (ESI+) m/z 412 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1CCNC1
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCCC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and pyrrolidine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:22]=[CH:21][C:12]([CH2:13][CH:14]3[S:18][C:17](=[O:19])[NH:16][C:15]3=[O:20])=[CH:11][C:10]=2[CH3:23])=[N:6][CH:7]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[O:19]=[C:17]1[NH:16][C:15](=[O:20])[CH:14]([CH2:13][C:12]2[CH:21]=[CH:22][C:9]([O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:33]([C:25]4[NH:24][C:32]5[C:27]([CH:26]=4)=[CH:28][CH:29]=[CH:30][CH:31]=5)=[O:34])=[CH:3][CH:4]=3)=[C:10]([CH3:23])[CH:11]=2)[S:18]1
Reactant: Cc1cc(CC2SC(=O)NC2=O)ccc1Oc1ccc(N)cn1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CC2SC(=O)NC2=O)ccc1Oc1ccc(NC(=O)c2cc3ccccc3[nH]2)cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 5-[4-(5-aminopyridin-2-yloxy)-3-methylbenzyl]thiazolidine-2,4-dione (150 mg, 0.46 mmol) in DMF (5 mL) were added indole-2-carboxylic acid (74 mg, 0.46 mmol), 1-hydroxybenzotriazole monohydrate (70 mg, 0.46 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg, 0.57 mmol), and the resulting solution was stirred for 5 days at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was then purified by silica gel column chromatography (chloroform:methanol=30:1). To the obtained powdery substance was added ethanol, the resulting solution was filtered and the filtrate was washed with ethanol, to thereby yield 100 mg of the title compound.