Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccc(O)nc4)c3c2)cc1OC
Reaction time: 0.33 h
Yield: 34 %

Procedure:
To 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2-ol, 3,4-dimethoxyphenyl boronic acid (1.3 equiv.) and dichlorobis (triphenylphosphino)palladium (ii) (6 mol %) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water, and a 2 M solution of sodium carbonate in water to achieve an overall concentration of the starting material of 0.10 M. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture extracted three times with ethyl acetate. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-ol as an off-white solid (34% yield). 1H NMR (DMSO-d6): δ 11.86 (broad s, 1H), 11.67 (broad s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.89 (dd, J=2.5, 10 Hz, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.23 (dd, J=2.0, 8.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.44 (d, J=9.0 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H); MS: m/z 348.1 [MH]+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([F:15])[C:8]([F:16])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O.CN(C)C=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([F:15])[C:8]([F:16])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
In 37 ml of toluene was dissolved 30 g (0.124 mole) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid, and 35 ml of thionyl chloride and 0.5 ml of N,N-dimethylformamide were added thereto. The mixture was refluxed by heating for 4 hours. After the reaction, toluene and excess thionyl chloride were removed under reduced pressure to obtain 2,4,5-trifluoro-3-difluoromethoxybenzoyl chloride.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=[O:5])#[N:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[N:9]1([C:4](=[O:5])[CH2:3][C:1]#[N:2])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: CCOC(=O)CC#N
Product: N#CCC(=O)N1CCOCC1
Yield: 76.9 %

Procedure:
Ethyl cyanoacetate (5.33 mL, 50 mmol) and morpholine (17.49 mL, 0.2 mol) were gently refluxed at 90° C. in an oil bath for 2 days. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with 50% acetone in n-hexane. 5.93 g of the compound was obtained. MS (DCI) m/e 155 (M+H)+, 172 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 4.03 (s, 2H), 3.53-3.59 (m, 4H), 3.42-3.45 (m, 2H), 3.32-3.35 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:17]=[C:18]=O)(=O)=O.C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]#[N:17])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.1 g 6-nitro-1H-indole are dissolved in 100 ml acetonitrile and cooled to 0° C. A solution of 3.2 ml chlorosulphonyl isocyanate in 25 ml acetonitrile is added dropwise and the mixture is stirred for 2 hours. Then a solution of 5 ml triethylamine in 25 ml acetonitrile is added dropwise. The mixture is stirred for 1 hour at ambient temperature and for 50 minutes at 80° C. Then the solvents are eliminated in vacuo, the residue is extracted from cold water, the solid is suction filtered and washed successively with water, saturated sodium hydrogen carbonate solution and water. The solid thus obtained is dried in the desiccator. Then the solid is taken up in 500 ml dichloromethane/methanol 95:5 and stirred with some aluminium oxide. It is suction filtered through a thin layer of aluminium oxide and washed with 400 ml dichloromethane/methanol 95:5. The filtrate is evaporated down in vacuo and the residue is dried in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]2[NH:15][N:16]=[CH:17][C:5]=12)[CH3:2].I[CH2:19][CH2:20][CH2:21][C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:12][C:10]([C:9]1[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:17]=[N:16][N:15]([CH2:23][CH2:22][CH2:21][C:20]#[CH:19])[C:6]2=[N:7][CH:8]=1)=[O:11])[CH3:14]
Reactant: C#CCCCI
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCn1ncc2c(OCC)c(C(=O)OCC)cnc21
Reaction time: 1 h
Yield: 111.9 %

Procedure:
A mixture of 3.78 g of ethyl 4-ethoxy-1H-pyrazolo-[3,4-b]pyridine-5-carboxylate, 3.90 g of 1-iodo-4-pentyne, and 6.68 g of pulverized anhydrous potassium carbonate in 27 ml of dry DMF was stirred at 50°-60° for 1 hr. The mixture was cooled, poured into water, and the resulting mixture extracted with EtOAc. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to leave 5.42 g of a dark oil which slowly crystallized. This material was chromatographed over silica gel using EtOAc/hexane 1:2 (v/v) as the eluant to give 3.03 g (62%) of the title compound as a white solid. A small quantity was recrystallized from toluene to give white crystals, m.p. 84°-85.5°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>O1CCCC1>[C:31]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=2)=[CH:22][CH:21]=1)(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(O)cc2)on1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-hydroxyphenyl)isoxazole (0.15 g) was dissolved in tetrahydrofuran (1.5 ml), and triethylamine (0.07 ml) and acetyl chloride (0.04 ml) were added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (0.12 g, 71%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.ClC1C=C(Cl)N=[C:23]([C:28]2C=CC=[CH:30][CH:29]=2)N=1.ClC1C=C(Cl)N=C(CCCCCCCCCC)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:23][CH2:28][CH2:29][CH3:30])[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH:3]=1
Reactant: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: CCCCCCCCCCc1nc(Cl)cc(Cl)n1
Product: CCCCCCCCCCc1nc(Cl)cc(OCCC(C)C)n1

Procedure:
The compound of Example 24 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-decylpyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][C:9]([CH3:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:30][C:31](=[O:34])[CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:32][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:34])[C:12]2[C:7](=[CH:8][C:9]([CH3:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)c1cc(O)c2ccc(C)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5.00 g 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 35 ml of DMF, 8.25 g of cesium carbonate and 5.80 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 12 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 10.00 g.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2]CCCCCCCCCCCC.[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:18]1([C@H:1]([OH:15])[CH3:2])[CH:17]=[CH:16][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCC
Reactant: CCCCCCCCCCCCCCO
Product: C[C@@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
To the distillation residue were added 270 g of n-tetradecanol, 450 ml of hexane, and 10 g of Lipase OF. After regulating the particle size of the lipase by ultrasonication in the same manner as above, the mixture was stirred at 50° C. and 350 rpm for 72 hours to carry out interesterification. Hexane was evaporated under reduced pressure from the reaction mixture, and the residue was subjected to simple distillation at 90° C. and 3 mmHg to give highly pure (R)-(+)-1-phenylethanol in a free form (yield: 87%; chemical purity: 100%; optical purity: 100% ee).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:21][O:22][C:23](=[O:43])[CH:24]([NH2:42])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>>[CH3:21][O:22][C:23](=[O:43])[CH:24]([NH:42][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:19])=[CH:8][N:7]=2)=[CH:18][CH:17]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)C(N)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: COC(=O)C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid (283 mg, 1.0 mmol) and 2-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester (360 mg, 1.0 mmol) following general procedure A. (580 mg) 1H-NMR(400 MHz, CD3COCD3): 3.24 (dd, 1H), 3.39 (dd, 1H), 3.74 (s, 3H), 4.98 (m, 1H), 6.64 (d, 1H), 7.50 (m, 2H), 7.60 (m, 2H), 7.69 (m, 3H), 7.78 (d, 2H), 7.88 (d, 2H), 7.98(m, 2H), 8.15 (m, 2H); LC/MS (m/z): 589 (M+1)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[CH3:18][S:19]([CH2:22][CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:21])=[O:20]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:23][CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:10]=1)=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCCS(C)(=O)=O)cc1
Reactant: O=C(Nc1nccs1)c1c[nH]c2ccccc12
Product: CS(=O)(=O)CCn1cc(C(=O)Nc2nccs2)c2ccccc21

Procedure:
The title compound was prepared using 1H-indole-3-carboxylic acid thiazol-2-ylamide and toluene-4-sulfonic acid 2-methanesulfonyl-ethyl ester as R5X.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C.CCOCC>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:22][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=1
Reactant: CCCCCC(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 99.6 %

Procedure:
t-Butyidimethylsilylchloride (2.49 g, 16.5 mmol) was added to a solution of the alcohol 6 (3.6 g, 14.0 mmol) and imidazole (1.91 g, 28.0 mmol) in DMF (22 mL) at 23° C. The reaction was stirred for 16 h, diluted with Et2O and washed with 1 N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 100% hex) afforded 5.18 g (63%) of the silyl ether 7 as a clear, colorless oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:39][CH:40]([F:42])[F:41])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ncc2c(c1OC1CCN(CC(F)F)CC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 65 °C
Yield: 95.6 %

Procedure:
To a suspension of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (450 mg, 0.88 mmol) in THF (8 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (282 mg, 1.32 mmol) in THF (1 mL), followed by DIPEA (250 μL). The resultant reaction mixture was heated at 65° C. for 7 hours, then concentrated in-vacuo. The residue was triturated with ethyl acetate to afford the title compound as a pale yellow solid (485 mg, 96%). 1H NMR (300 MHz, DMSO-d6): 9.46 (s, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.70 (d, J=2.3 Hz, 1H), 8.24-8.23 (m, 2H), 7.78 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 6.13 (tt, J=55.8, 4.3 Hz, 1H), 4.85-4.85 (m, 1H), 3.17-3.12 (m, 2H), 2.75 (td, J=15.7, 4.3 Hz, 2H), 2.37 (t, J=10.9 Hz, 2H), 2.08-2.07 (m, 2H), 1.96-1.95 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])(C)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][C@H:24]([C:28](=[O:33])N(OC)C)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][C@H:24]([C:28]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:33])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(Br)cn1
Reactant: CON(C)C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
5-Bromo-2-methoxypyridine (247 mg, 1.31 mmol) was dissolved in toluene (6 mL) and cooled to −75° C. t-Butyl lithium (0.77 mL of 1.7 M in pentane, 1.3 mmol) was added dropwise. Stirring was continued at the same temperature for 15 min and then in an ice bath for 5 min. The reaction was cooled to −75° C. and a solution of (S)-2-(methoxy-methyl-carbamoyl)-morpholine-4-carboxylic acid tert-butyl ester (300 mg, 1.09 mmol) in toluene (3 mL) was added dropwise over 5 min. The reaction was stirred at 0° C. for 1.25 h and then poured onto water. The mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (1:1 EtOAc/heptane eluent) to afford (S)-2-(6-methoxy-pyridine-3-carbonyl)-morpholine-4-carboxylic acid tert-butyl ester (315 mg, 89%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.97-3.25 (m, 2H) 3.63-3.76 (m, 1H) 3.85-3.97 (m, 1H) 4.02 (s and overlapping m, 4H) 4.10-4.32 (m, 1H) 4.50-4.66 (m, 1H) 6.80 (dd, J=8.87, 0.54 Hz, 1H) 8.17 (dd, J=8.87, 2.42 Hz, 1H) 8.91 (d, J=2.42 Hz, 1H).
Reaction SMILES: C(O[CH:6]([O:17]CCCC)[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)CCC.[CH:22]([Mg]Br)=[CH2:23].[Cl-].[NH4+]>O1CCCC1>[CH3:13][C:11]1[CH:10]=[C:9]2[C:8](=[C:7]([CH:6]=[O:17])[CH:12]=1)[NH:14][CH:23]=[CH:22]2
Reactant: CCCCOC(OCCCC)c1cc(C)ccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C=O)c2[nH]ccc2c1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
Dissolve 2-Dibutoxymethyl-4-methyl-1-nitrobenzene (13.957 g, 47.373 mmol) in anhydrous tetrahydrofuran (474 mL) under nitrogen, and cool the solution to −40° C. Add vinylmagnesium bromide (190 mL, 190 mmol, 1.0 M in tetrahydrofuran) at 40° C. with stirring. Stir the reaction mixture for 40 minutes and add saturated aqueous ammonium chloride. Extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over sodium sulfate, filter, and concentrate. Dissolve the residue in tetrahydrofuran (160 mL) and cool to 0° C. Add aqueous 0.5 molar hydrochloric acid (20 mL) and stir the mixture at 0° C. for 1 hour. Add saturated aqueous sodium hydrogen carbonate (200 mL) and extract the aqueous layer with ethyl acetate (3×200 mL). Combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify by flash column chromatography (silica gel, 5% ethyl acetate/hexane) to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C:14]#[CH:15]>O1CCOCC1>[Cl:8][C:7]1[C:2]([NH:12][CH2:13][C:14]#[CH:15])=[N:3][CH:4]=[C:5]([C:9]([OH:11])=[O:10])[N:6]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)n1
Reactant: C#CCN
Solvent: C1COCCO1
Product: C#CCNc1ncc(C(=O)O)nc1Cl

Procedure:
A mixture of 2,3-dichloropyrazine-5-carboxylic acid (19.3 g, 0.100 mole) and 3-amino-1-propyne (1.10 g, 0.20 mole) in 100 ml dioxane is refluxed for 24 hours, cooled and concentrated under vacuum. The residue is partitioned between aqueous sodium bicarbonate and chloroform and the aqueous extract neutralized with acetic acid to give a precipitate of 3-chloro-2-(2-propyn-1-ylamino)pyrazine-5-carboxylic acid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([N:15]([CH2:20][CH:21]=[CH2:22])[CH2:16][C:17]([OH:19])=[O:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>ClCCl.CO>[CH3:1][O:18][C:17](=[O:19])[CH2:16][N:15]([CH2:20][CH:21]=[CH2:22])[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9]
Reactant: C=CCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: C=CCN(CC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trimethylsilyldiazomethane (2N, in hexane) (12 ml) was added dropwise to a solution of N-Boc-allylglycine (3.09 g) in dichloromethane/methanol (2/1) mixture (30 ml), and the resulting mixture was stirred at room temperature for 3 hours. After concentrating the reaction solution, the residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=20/1-10/1) to obtain N-Boc-allylglycine methyl ester (3.11 g). NMR (H1, CDCl3): δ 2.43-2.55 (2H, m), 3.72 (3H, s), 4.34-4.39 (1H, brm), 5.02 (1H, brs), 5.09-5.13 (2H, m), 5.62-5.72 (1H, m)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31]>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: C[C@@H](N)c1ccccn1
Solvent: CC#N
Product: COc1cc2c(N[C@H](C)c3ccccn3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 110 °C
Reaction time: 4 h

Procedure:
The mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide (for a preparation see intermediate 40, 6 g, 18 mmol) was reacted with (1R)-1-(2-pyridinyl)ethanamine (2 eq., 4.43 g, 36 mmol) in CH3CN (100 ml) and was stirred at 110° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over Na2SO4 and concentrated to dryness to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-4-{[(1R)-1-(2-pyridinyl)ethyl]-amino}-3-quinolinecarboxamide which was used in the next step without purification. The carboxamide intermediate (6 g) was treated with an excess of [bis(trifluoroacetoxy)iodo]benzene (19.35 g, 45 mmol) in CH3CN (100 ml), the mixture was stirred at room temperature overnignt. The reaction mixture was concentrated in vacuo, the resulting residue was dissolved in DCM and washed with water. The crude product was purified by flash chromatography on silica gel (DCM/MeOH, 95:5), the resulting compound was dissolved in DCM and precipitated from diethylether to give the title compound as an off-white powder (2.5 g, 33%)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33]>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:30]4[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: O=C1CNCCN1
Reactant: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 170 °C
Reaction time: 3 h

Procedure:
6-Chloro-3-[(S)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate Q, 50 mg, 0.144 mmol), KF, 42.6 mg, 0.719 mmol) and piperazin-2-one (44.5 mg, 0.431 mmol) were suspended in NMP (0.3 mL). The RM was stirred at 170° C. for 3 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in EtOAc/Pentane to afford the title compound as a light brown solid (tR 3.63 min (conditions 5), (tR 10.82 min (conditions 2), MH+=412.2, 1H-NMR in DMSO-d6: 8.07 (s, 1H); 8.03 (s, 1H); 7.79 (d, 1H); 7.52 (s, 1H); 7.36 (d, 1H); 7.02 (d, 1H); 4.85 (m, 1H); 3.95 (d, 1H); 3.95 (s, 3H); 3.73 (d, 1H); 3.54 (m, 2H); 3.17 (m, 2H); 1.79 (d, 3H)).