Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14]O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[B-](F)(F)(F)[F:23].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14][F:23])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: F[B-](F)(F)F
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (3.4 g, 11.8 mmol; Intermediate 29, Step 1) in dry dichloromethane (100 mL), was added triethylamine-3HF (7.6 g, 47.2 mmol). XtalFluor-E (8.0 g, 34.9 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether), and then re-crystallized from petroleum ether to afford the title compound (1.3 g). 1H NMR (300 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.58 (d, 1H), 7.44 (dd, 1H), 5.89 (dd, 1H), 4.60 (dt, 2H), 3.91-3.85 (m, 1H), 3.80-3.69 (m, 1H), 2.93 (dt, 2H), 2.46-2.28 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.67 (m, 1H), 1.60-1.52 (m, 2H); LCMS: 291 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>N1C=CC=CC=1>[N:20]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[S:13][C:12]=1[C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:24]=[C:23]([O:22][CH3:21])[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)cc(-c2nc3ccncc3s2)c1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)cc(-c2nc3ccncc3s2)c1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Methyl 3-amino-5-(thiazolo[5,4-c]pyridin-2-yl)benzoate (150 mg, 0.526 mmol) was mixed together with 3,4,5-trimethoxybenzoyl chloride (121 mg, 0.526 mmol) in 1 mL of pyridine. The reaction mixture was reacted in a Biotage microwave reactor at 160 degrees for 10 min. It was then cooled to room temperature and concentrated. The resulting residue was purified by chromatography using a 9:1 mixture of CH2Cl2 to MeOH to afford 90 mg of methyl 3-(thiazolo[5,4-c]pyridin-2-yl)-5-(3,4,5-trimethoxybenzamido)benzoate(36% yield) (MS, M++H=480).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][N:20]3[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:21]3)=[CH:37][CH:38]=2)[N:4]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyloxazole (312 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (687 mg, yield: 87%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (5:6, volume ratio).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3].Cl>CO>[CH2:1]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3]
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(N)n1
Yield: 75.1 %

Procedure:
To a solution of 7-[2-(2-propynyl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(2.0 g) in methanol (14 ml) was added conc.hydrochloric acid (0.3 g) and the mixture was stirred for 3.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with conc.hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:12][C:11]([C:29](OC)=[O:30])=[N:10]1.[F-].[K+].Cl.[CH:36]([OH:39])([CH3:38])[CH3:37]>>[NH2:26][S:25]([C:21]1[CH:20]=[C:19]([C:16]2[S:15][C:14]([C:13]3[N:9]([C:3]4[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[C:11]([C:29]([O:39][CH:36]([CH3:38])[CH3:37])=[O:30])[CH:12]=3)=[CH:18][CH:17]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:28])=[O:27]
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(N)(=O)=O)c3)s2)n(-c2cc(Cl)ccc2Cl)n1
Reactant: CC(C)O
Agent: Cl
Agent: [F-]
Agent: [K+]
Product: CC(C)OC(=O)c1cc(-c2ccc(-c3cccc(S(N)(=O)=O)c3)s2)n(-c2cc(Cl)ccc2Cl)n1
Temperature: 82.5 °C

Procedure:
Into a 25 mL flask was weighed 114 mg (224 mmol) of methyl 1-(2,5-dichlorophenyl)-5-(5-(3-sulfamoylphenyl)thiophen-2-yl)-1H-pyrazole-3-carboxylate, 156 mg of KF, 4 mL of isopropyl alcohol, and 200 μL of concentrated HCl. The reaction was heated at 80-85° C. for 3 days. The reaction was then washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. Product was further purified by silica gel flash chromatography (Jones Flashmaster, 25 g SiO2, gradient elution from 20% ethyl acetate to 60% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless powder, yield: 53.3 mg (44%). 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.83 (d, J=8 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.59 (s, 1H), 7.44-7.51 (m, 3H), 7.21 (d, J=4 Hz, 1H), 7.13 (s, 1H), 6.81 (d, J=4 Hz, 1H), 5.33 (heptet, J=6 Hz, 1H), 5.08 (s, 2H), 1.41 (d, J=7 Hz, 6H); MS (ES): 536 [M+H]+.
Reaction SMILES: [Na].Cl[C:3]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:13][OH:14]>>[CH:10]([O:9][C:8]1[C:3]([O:14][CH3:13])=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Oc1cccnc1Cl
Reactant: CO
Agent: [Na]
Product: COc1ncccc1OC(C)C
Temperature: 150 °C

Procedure:
To a solution of methanolate obtained by dissolving sodium (534 mg, 23.25 mmol) in MeOH (8 ml) was added a solution of 2-chloro-3-isopropoxy-pyridine (Stage 93.1.4, 1.14 g, 6.64 mmol) in MeOH (2 ml). The reaction mixture was heated at 150° C. by microwave irradiation for 25 min then concentrated and quenched with EtOAc and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound as an oil (HPLC: tR 2.66 min (Method A); M+H=264 MS-ES)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:35])[C:11](C(O)=O)=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([N:45](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:15]([C:14]1[N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:12]=[C:11]([NH2:45])[C:10](=[O:35])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CCN(CC)CC
Reactant: COC(Cn1cc(C(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(Cn1cc(N)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1 g) obtained in Example 161, Step 4 in tetrahydrofuran (15 ml)-toluene (15 ml) were added triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (8 ml). Triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) were added again and 2 hr later, and 3 hr later, triethylamine (1.22 ml, 0.61 ml) and diphenylphosphoryl azide (0.94 ml, 0.47 ml) were respectively added, and stirring was continued. After confirmation of disappearance of the starting material, 9-fluorenylmethanol (7.7 g) and toluene (10 ml) were added, and the mixture was stirred under reflux with heating. After 20 min, triethylamine (2.5 ml) was added, and stirring was continued with heating for 1.5 hr. The mixture was concentrated, water was added to the residue and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-chloroform:methanol=15:1) to give 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (886 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C#N)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (65 mg, 81%), MS (ISP) m/z=320.6 [(M+H)+], mp 295° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]=[O:14].C(=O)=O.CC(C)=O.[NH4+].[Cl-]>C1COCC1>[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:14]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(C(O)c2ccc(Cl)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of (4-chlorophenyl)magnesium bromide (1M in Et2O, 81 ml, 81 mmol) in THF (200 ml) was added drop wise a solution of 2-chloro-5-nitrobenzaldehyde (10 g, 53.9 mmol) in THF (100 ml) at −78° C. (dry ice/acetone bath). After the addition, the reaction mixture was further stirred at −78° C. for 1 h then 10 min at 0° C. (ice bath). A saturated aqueous NH4Cl solution (400 ml) was added and the resulting mixture was extracted with AcOEt (2×400 ml). The combined organic layers were washed with brine then dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME 95:5→6:4) to yield the title compound (14.4 g, 48.4 mmol, 90%) as a beige solid. TLC: RF=0.80 (heptane/DCM/TBME 1:1:2); HPLC: AtRet=2.43 min; LC-MS: m/z not detected; 1H NMR (400 MHz, CDCl3): 6.20 (s, 1H), 7.36 (s, 4H), 7.53 (d, J=8.6, 1H), 8.13 (dd, J=8.8, 2.9, 1H), 8.66 (d, J=2.7, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH:23]4[C:27]([O:29]C(C)(C)C)=[O:28])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:34])[CH2:9]2)=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1.CC#N.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH:23]4[C:27]([OH:29])=[O:28])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C@H:10]([CH3:34])[CH2:9]2)=[C:4]([C:35]([F:38])([F:36])[F:37])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCCC2C(=O)OC(C)(C)C)s1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCCC2C(=O)O)s1
Temperature: 25 °C

Procedure:
tert-butyl 1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)pyrrolidine-2-carboxylate (316.0 mg, 0.547 mmol), CeCl3.7H2O (815.0 mg, 2.19 mmol) and KI (363.0 mg, 2.19 mmol) charged to a microwave vial were added with CH3CN (12 mL) and water (0.2 mL). The reaction mixture was subjected to microwave irradiation at 110° C. for 1 hour. This reaction was repeated twice. Both reaction mixtures were then combined and the supernatant clear solution was transferred into a flask, added with CH2Cl2 and stirred at room temperature. Solid was filtered off, filtrate concentrated, dried under high vacuum to yield crude 1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)pyrrolidine-2-carboxylic acid which will be used as it is for the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[CH:7]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.O>C(O)C>[CH:16]1([NH:19][C:11]([C:8]2[CH:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[O:10][N:9]=2)=[O:13])[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cc(-c2cccs2)on1
Reactant: NC1CC1
Solvent: CCO
Solvent: O
Product: O=C(NC1CC1)c1cc(-c2cccs2)on1
Temperature: 80 °C
Yield: 64 %

Procedure:
To a solution of ethyl 5-(thiophen-2-yl)isoxazole-3-carboxylate (220 mg, 1 mmol) in absolute ethanol (5 mL) was added cyclopropylamine (285 mg, 5 mmol). The reaction was sealed and heated to 80° C. for 24 hours. The reaction was allowed to cool to room temperature and water (1 mL) was added. The product was collected by vacuum filtration as a white crystalline solid (150 mg, 64% yield). δH (400 MHz, d6 DMSO): 8.85 (1H, d), 7.83 (1H, d), 7.76 (1H, d), 7.24 (1H, d), 7.18 (1H, s), 2.83 (1H, m), 0.58-0.71 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:3](/[CH:8]=[N:9]/[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>ClCCl>[C:25]([O:28][C@H:29]1[C@@H:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:30]1=[O:31])(=[O:27])[CH3:26]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(/N=C/c2ncccc2F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A solution (2.29 l) of N-[(E)-(3-fluoro-2-pyridyl)methylidene]-4-methoxyaniline (449 g) and triethylamine (204 g) in dichloromethane was cooled to −10° C. Then acetoxyacetyl chloride (250 g) was added dropwise thereinto and the resultant mixture was stirred at the same temperature for 30 minutes. Then it was heated to room temperature and stirred for 16 hours. The liquid reaction mixture was washed with water and the solvent was concentrated under reduced pressure to thereby give a crude product (723 g). This crude product was recrystallized from a solvent mixture of ethanol (6.9 l) and ethyl acetate (350 ml) to thereby give the title compound (486 g) as brown crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: NCCCC(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C(O)CCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 78.8 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and 4-aminobutyric acid (0.268 g, 0.0026 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.57 g (79%) 122 as a very pale orange powder: mp=144-146° C.; Rf0.62 (A): Rf0.87 (C): Rf0.78 (D): IR (cm−1): 3000-3250 (OH), 3219 (C═CH), 2953 (C—H), 1778 (C═O), 1716 (C═O), 1667 (C═O), 1615 (C═C), 1548 (N═O), 1442 (C═C), 1395 (C—O), 1355 (N═O), 1189 (C—O), 723 (C═CH); MS m/z (rel intensity) 313 (100), 278 (65), 277 (42), 191 (71).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(F)c4)cc23)CC1
Yield: 67.2 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.15 mMol) 3-fluorobenzoic acid, 11.8 mg (67%) of the title compound were recovered.
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16](F)(F)[C:17]([OH:19])=O.C(O)(=O)C[SH:24]>ClCCl>[CH:1]([CH2:16][C:17]([OH:19])=[S:24])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)CS
Reactant: OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: OC(=S)CC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of benzhydrol (90 g, 0.488 mol) and trifluoroacetic acid (90 mL) in dichloromethane (300 mL) was added thioglycolic acid (40 g, 0.488 mol) in dichloromethane (60 mL) drop wise over 20 minutes. The reaction was completed in one hour. The solvent was removed in vacuo to give a crude solid, which was dried overnight under high vacuum. The solid was treated with 2 N NaOH (1.0 L) and washed with t-butylmethylether (200 ml) to remove non carboxylic acid impurities. The aqueous solution was then acidified with concentrated HCl and the resulting precipitate was collected, washed with water and dried to give benzhydrylthioacetic acid (128.5 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:36][CH:35]=2)=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1nccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
A mixture of 1-methyl-1H-pyrazol-5-carboxylic acid (1.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.82 g), 1-hydroxybenzotriazole monohydrate (1.70 g) and chloroform (20 mL) was stirred at a room temperature for 15 minutes. Thereafter, 4-aminobenzotrifluoride (1.27 g) was added to the reaction solution, and the obtained mixture was then stirred for 24 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, and the residue was then purified by column chromatography (chromatorex NH, hexane:ethyl acetate=4:1), so as to obtain the title compound (1.00 g) in the form of a colorless solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:22][C:23](C)([O-])[CH3:24].[K+].IC(C)C>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:23]([CH3:24])[CH3:22])[CH:17]=[CH:16]2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CC(C)n1ccc2cc(OCCCO[Si](C)(C)C(C)(C)C)ccc21
Reaction time: 0.17 h
Yield: 38 %

Procedure:
Dissolve 5-[3-(tert-butyldimethylsilyloxy)propoxy]-1H-indole (1.0 g, 0.327 mmol) in N,N-dimethylformamide (20 mL) under nitrogen. Add 3.6 mL potassium tert-butoxide (1M solution in THF, 1.1 equiv) and stir 10 minutes, then add 2-iodopropane (0.36 mL, 1.1 eq) and stir for 30 minutes. Dilute with ethyl acetate and wash with water then brine. Dry over magnesium sulfate, filter and concentrate. Purification by column chromography (hexanes to 4:1 hexanes:ethyl acetate) affords 0.43 g product (38%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 0.00 (s, 6H), 0.83 (s, 9H), 1.40 (d, J=6.83 Hz, 6H), 1.86 (m, 2H), 3.74 (m, 2H), 3.98 (m, 2H), 4.64 (m, 1H), 6.29 (d, J=2.93 Hz, 1H), 6.71 (m, 1H), 6.99 (d, J=1.95 Hz, 1H), 7.36 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=2)=[C:4]([F:37])[CH:3]=1.C(N(CC)CC)C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:32])[CH3:33])[CH:26]=2)=[C:4]([F:37])[CH:3]=1
Reactant: C1COCCN1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CN5CCOCC5)sc4n3)c(Cl)cc2F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
N-[4-Chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (3.0 mL), triethylamine (85.6 μL, 0.621 mmol) and morpholine(54.3 μL, 0.621 mmol) were added, and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (101 mg, 80%) as a colorless amorphous powder.