Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C([O-])(O)=O.[Na+].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>[N:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:7]=[C:6]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[CH:5]=[C:4]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:3]=2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(-c4ccncc4)n3)cccc2s1
Temperature: 125 °C

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide (137 mg, 0.29 mmol, Example 7(d)), 4-pyridinyl boronic acid (40 mg, 0.32 mmol, Aldrich), Pd(PPh3)4 (24 mg, 0.02 mmol, Aldrich) and 2N Na2CO3 (0.5 mL) in 1,2-dimethoxyethane (1.5 mL) was heated at 125° C. in a microwave synthesizer for 20 min. The reaction mixture was cooled to room temperature, diluted with sat. aqueous solution of NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (gradient 50-90% EtOAc/hexane) gave the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 508 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)CCC.[Li+].[Cl-].C(C1C(C)=CC=C(O)C=1C(C)(C)C)(C)(C)C>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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(O)c(C(C)(C)C)c1C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnccn2)c(C(F)(F)F)cc1N
Temperature: 120 °C
Reaction time: 36 h
Yield: 38.4 %

Procedure:
A solution containing 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (750 mg, 2.17 mmol), 2-tributylstannylpyrazine (1.0 g, 2.7 mmol) and (Ph3P)4Pd (125.6 mg, 0.109 mmol) in dioxane (40 mL) was heated at 120° C. for 17 h. LiCl (276.4 mg, 6.5 mmol) was added and the reaction mixture was refluxed for 1.5 h prior to the addition of di-t-butyl-p-cresol (188 mg, 0.85 mmol) and another portion of (Ph3P)4Pd (251.2 mg, 0.22 mmol). Heating was continued for 16 h, for a total reaction time of 36 h. After cooling to r.t., the solvent was removed in vacuo and the residue was purified by flash chromatography (200 g silica gel, hexanes→EtOAc:hexanes (3:7 to 1:1)). The fractions containing the product were combined and concentrated in vacuo. The resultant oil was further purified by partioning between CH3CN and hexanes. The acetonitrile layer was concentrated in vacuo to furnish the title compound (248 mg, 38%) as a solid. API-ES: m/z 298 [M+H]+, rt 4.18 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:32]=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:34][CH:35]=3)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)[CH:12]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:32]=[C:33]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:34][CH:35]=4)=[CH:27][CH:26]=3)[CH2:13][CH2:14]2)=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Yield: 99.7 %

Procedure:
The product from example 40C (1.37 g, 2.153 mmol), in ethanol (10 mL) and THF (10 mL) then added platinum(IV) oxide (196 mg, 0.862 mmol) and a hydrogen balloon and stirred the solution at room temperature for 48 h. The reaction was then treated according to the procedure in Example 39G to provide the title compound (1.3 g, 100%) as a mixture of stereoisomers.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH2:23])[CH:22]=2)[CH:12]=[N:13][CH:14]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:23][C:5](=[O:7])[CH3:6])[CH:22]=2)[CH:12]=[N:13][CH:14]=1
Reactant: Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Add acetic anhydride (113 mg, 1.11 mmol) to a solution of 5-(5-chloropyridin-3-ylethynyl)-2-fluorophenylamine, (prepared as described in EXAMPLE 190) (0.275 g, 1.11 mmol) in pyridine (4 mL). Stir the mixture at room temperature under nitrogen for 18 h then concentrate. Purify by silica gel chromatography, eluting with a gradient of 75:25 to 50:50 with hexanes:ethyl acetate, followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (240 mg, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[K+].[K+].N(C([O-])=O)=NC([O-])=O.C(O)(=O)C>CO>[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH2:9][CH3:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@]1(N)C[C@H]1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (400 mg, 1.57 mmol) was dissolved in methanol (5 ml) and added to a suspension of azodicarboxylic acid dipotassium salt (1.46 g, 7.5 mmol; cf. D. J. Pasto et al., Organic Reactions 40 (1991), 91-155) in methanol (10 ml). Acetic acid (1.12 g, 18.8 mmol) was added in the course of 10 min and the mixture was stirred for 1 h at room temperature. Azodicarboxylic acid dipotassium salt (1.46 g) and acetic acid (1.12 g) were added once again and the mixture stirred for 1 h. LC/MS analysis then indicated complete conversion. The volatiles were evaporated, the residue was partitioned between EA and a saturated sodium hydrogencarbonate solution, and the combined organic extracts were dried over sodium chloride, decanted over a small plug of silica gel and evaporated to dryness. The obtained intermediate was dissolved in a mixture of DCM (5 ml) and TFA (1 ml) and stirred for 1 h at room temperature. The volatiles were evaporated, and the residue was partitioned between diethyl ether and saturated sodium hydrogencarbonate solution. The combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness to yield the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Zn+2:5].[NH2:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9]>O>[NH2:6][C@H:7]([C:10]([O-:12])=[O:11])[CH2:8][SH:9].[Zn+2:5].[NH2:6][C@H:7]([C:10]([O-:12])=[O:11])[CH2:8][SH:9]
Reactant: N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Zn+2]
Solvent: O
Product: N[C@@H](CS)C(=O)[O-]

Procedure:
Basic zinc carbonate (10 g) was added to a solution of cysteine in water (14.92 g/100 ml) and was heated under reflux for 16h with stirring. The off-white microcrystalline solid was collected by filtration, washed with water and dried in air. The empirical formula for the complex, as determined by thermogravimetric analysis, was; Zn[SCH2CH(NH2)CO2]. This empirical formula was confirmed by matching the Fourier transform infra-red spectrum for the product with a reference spectrum for this complex, Shindo and Brown, J.Am.Chem.Soc. 87 (1965) 1904-1909.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@@H:10]1[NH:14][C:13]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[NH:12][C:11]1=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH4+].[Cl-]>C1COCC1>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][C:13]2([N:12]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:11](=[O:27])[C@H:10]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:14]2)[CH2:19][CH2:18]1)=[O:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (1.26 g, 52.5 mmol) was added at RT to a solution of tert-butyl 3-(S)-benzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (12.1 g, 35 mmol) in THF (250 ml). After stirring for 1 h at 0° C., benzyl chloride (4.9 g, 38.5 mmol) was added dropwise, and the mixture was allowed to warm to RT and heated for 60 h under reflux. Subsequently, benzyl chloride (2.4 g, 19 mmol) was again added and the mixture was heated under reflux for a further 16 h. The reaction mixture was treated with aqueous saturated NH4Cl solution (20 ml) and extracted with EA (3×50 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was distilled off. Workup was carried out by means of column chromatography and afforded tert-butyl-1,3-(S)-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate in a yield of 13.5 g (88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[O:11][CH2:10][CH2:9][NH:8][C:7]2=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)([O-])=O.[C:17]1([CH3:40])[CH:22]=[CH:21][C:20]([S:23](NC2C=C3C(=C(C(O)=O)C=2)NCCC3)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[C:17]1([CH3:40])[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:4]2[CH:5]=[C:6]3[O:11][CH2:10][CH2:9][NH:8][C:7]3=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1NCCO2
Reactant: Cc1ccc(S(=O)(=O)Nc2cc3c(c(C(=O)O)c2)NCCC3)cc1
Product: Cc1ccc(S(=O)(=O)Nc2cc3c(c(C(=O)O)c2)NCCO3)cc1
Yield: 5.3 %

Procedure:
The title compound was prepared (5.3% yield) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine-5-carboxylic acid by the same procedure as in Examples 31 and 32 (b). This compound was recrystallized form ethanol to give colorless crystals, mp 213°-215° C.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[OH:5][C:6]([C:12]1[CH:25]=[CH:24][C:23]2[C:14](=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[CH:18][CH:17]=[N:16]3)[N:13]=1)([CH3:11])[C:7]([CH3:10])([CH3:9])[CH3:8]>>[CH3:3][O:5][C:6]([C:12]1[CH:25]=[CH:24][C:23]2[C:14](=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[CH:18][CH:17]=[N:16]3)[N:13]=1)([CH3:11])[C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CI
Reactant: CC(C)(C)C(C)(O)c1ccc2ccc3cccnc3c2n1
Agent: [H-]
Agent: [Na+]
Product: COC(C)(c1ccc2ccc3cccnc3c2n1)C(C)(C)C
Yield: 55.2 %

Procedure:
By employing General Procedure II, NaH (0.008 g, 0.3 mmol), methyl iodide (0.020 mL, 0.3 mmol), and the corresponding 1-hydroxy-1,2,2-trimethylpropyl phenanthroline (0.023 g, 0.08 mmol), prepared as described by Example 5, were reacted to provide 0.013 g (55% yield) of the title methyl ether as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.23 (dd, J=4.50, 1.80 Hz, Hp9), 8.23 (dd, J=7.80, 1.80 Hz, Hp7), 8.17 (d, J=8.70 Hz, Hp4), 7.88 (d, J=8.40 Hz, Hp3), 7.81 and 7.74 (two d, J=8.70 Hz, Hp5 and Hp6), 7.60 (dd, J=8.00, 4.40 Hz, Hp8), 3.21 (s, OCH3), 1.94 (s, CH3), 0.98 (s, (CH3)3); 13C NMR (75 MHz) δ163.79, 150.37, 145.12, 143.90, 135.97, 134.34, 128.82, 127.18, 126.47, 125.99, 122.53, 121.43, 86.16, 51.36, 38.83, 26.10, 17.78; IR (CHCl3) 2957 (C—H Ar), 2928 (CH), 857 (C—H Ar) cm−1; HRMS m/e Calcd for C19H23N2O (MH+): 295.1810, found, 295.1818.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([O:23][CH2:24][CH3:25])[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[C:5]([C:26]2C=CC=CC=2C)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:26][C:5]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C@H:17]([O:23][CH2:24][CH3:25])[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCn2c(C)ccc2-c2ccccc2C)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCO[C@@H](Cc1ccc(OCCn2c(C)ccc2C)cc1)C(=O)O
Reaction time: 10 h
Yield: 114.3 %

Procedure:
A mixture of substituted ester (prepared in example 2) (1.38 g), sodium hydroxide (3.0%, 15 mL) in methanol (20 mL) was stirred at 20° C. to 25° C. for 10 h. Methanol was evaporated under reduced pressure. The residue was diluted with water (20 mL) and was acidified with dilute hydrochloric acid. The product was extracted with ethyl acetate (3×20 mL) and washed with water (2×80 mL), brine (80 mL) and was dried over sodium sulfate to obtain an oily product (1.2 g, 94%). The crude product (3 g) was separated by column chromatography using silica gel using hexane:ethyl acetate (9:1) as an eluent to afford the pure title compound (0.75 g, 59%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]([C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)[CH2:15][O:16][CH2:17][C:18]1[N:19]=[CH:20][N:21]([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)[CH:22]=1>ClCCl>[CH3:8][S:9]([O:13][CH:14]([C:42]1[CH:43]=[CH:44][C:45]([C:46]#[N:47])=[CH:48][CH:49]=1)[CH2:15][O:16][CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4 mmol of triethylamine and 2.00 mmol of methanesulphonyl chloride are added to a solution of 1.00 mmol of 4-[1-hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloro-methane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is used without further purification in the next stage. Rf=0.43 (dichloromethane-methanol 95:5); Rt=4.46 (gradient I).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 90 °C
Yield: 103.6 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 1.0 g) and lithium hydroxide monohydrate (0.96 g) in dioxane (16 mL) and water (14 mL) was stirred and heated at 90° C. for 1 hour. After cooling, the mixture was concentrated under vacuum and the residue was diluted with water and neutralised to pH7 with formic acid. The mixture was then extracted with ethyl acetate, dried (Na2SO4) and filtered and the filtrate was evaporated to dryness to give (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylic acid (0.97 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:31])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:58][C:59]1[CH:60]=[C:61](B(O)O)[CH:62]=[CH:63][C:64]=1[F:65]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:25][CH2:26]4)=[CH:7][CH:8]=3)[C:3](=[O:31])[C:2]=2[C:62]2[CH:61]=[CH:60][C:59]([F:58])=[C:64]([F:65])[CH:63]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(Cl)cc2)CC1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2ccc(F)c(F)c2)=C3c2ccc(Cl)cc2)CC1
Yield: 50 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(4-chlorophenyl)-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10]C)=[CH:4][C:3]=1[F:12].Cl>CC(C)=O>[F:12][C:3]1[CH:4]=[C:5]([CH2:8][CH:9]=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC=Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CC(C)=O
Product: O=CCc1ccc(F)c(F)c1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a solution of 1,2-difluoro-4-(2-methoxy-vinyl)-benzene (5.5 g, 0.032 mol, from step (i) above) in 80 ml acetone was added 66 ml of 3 (M) HCl and stirred at 45° C. for 4 h. Acetone was evaporated under reduced pressure and the residue was
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2.[C:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.CN(C)C=O>O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=[O:14])[CH2:17][CH2:16][C:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:18])=[CH:7]2
Reactant: Cc1ccc(C)c2cc(C=O)ccc12
Reactant: C=CC(=O)c1ccc(C(=O)OC)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(C)ccc(C)c3c2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
A mixture of 1.0 g of 5,8-dimethyl-2-naphthaldehyde, 1.2 g of methyl 4-acryloyl-benzoate, 0.28 g of 3-benzyl-5-(2-hydroxymethyl)-4-methylthiazolium chloride, 0.88 ml triethylamine and 20 ml N,N-dimethylformamide was heated under stirring at 70° C. for 3 hours. After the reaction solution was left standing for cooling to room temperature, water was added thereto, and the reaction solution was extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated and the resulting crude crystals were washed with a mixed solvent of n-hexane and ethyl acetate to give 0.82 g of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([OH:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([OH:18])[C:2]([C:27]4[CH:28]=[N:29][N:30]([CH:32]5[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]5)[CH:31]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c2O)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A mixture of (S)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (1.00 g, 3.24 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.40 g, 6.37 mmol), sodium carbonate (0.686 g, 6.47 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.263 g, 0.32 mmol), 1,4-dioxane (15 mL), and water (5 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 70% ethyl acetate/petroleum ether) to afford (S)-tert-butyl 4-(4-(1-(cyclopropanecarbonyl)-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.400 g, 26%) as a dark red solid. MS (ESI, pos. ion) m/z 481 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([CH:40]=[CH:41][CH:42]=1)[C:14]([NH:16][C:17]1[C:18]([CH3:39])=[C:19]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([NH2:38])=[C:32]([CH:37]=2)[C:33]([O:35][CH3:36])=[O:34])=[O:27])[N:20]2[C:25]=1[CH:24]=[CH:23][CH:22]=[CH:21]2)=[O:15])(=O)C.Cl>O.CO.C(OCC)(=O)C.C(OCC)C>[NH2:38][C:31]1[CH:30]=[CH:29][C:28]([C:26]([C:19]2[N:20]3[C:25]([CH:24]=[CH:23][CH:22]=[CH:21]3)=[C:17]([NH:16][C:14](=[O:15])[C:13]3[CH:40]=[CH:41][CH:42]=[C:11]([OH:10])[CH:12]=3)[C:18]=2[CH3:39])=[O:27])=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(OC(C)=O)c3)c3ccccn23)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(O)c3)c3ccccn23)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
0.46 g (3.30 mmol) of potassium carbonate dissolved in 4 ml of water is added to the suspension of 0.80 g (1.65 mmol) of methyl 5-[(1-{[3-(acetyloxy)benzoyl]-amino}-2-methylindolizin-3-yl)carbonyl]-2-aminobenzoate in 16 ml of methanol. The reaction medium is stirred at ambient temperature for 1 hour, it gradually becomes homogenized. It is diluted with ethyl acetate and acidified with a molar solution of hydrochloric acid. The two phases are separated. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is taken up in ethyl ether and then filtered and dried. 0.61 g (84%) of a greenish yellow powder is obtained.