Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9]2)[CH3:2].O1CCCC1.CO.[OH-].[K+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9]2)[CH3:2]
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
To a mixture of methyl 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (0.65 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added a solution of potassium hydroxide (85%, 0.33 g) in water (5 mL). The mixture was stirred at room temperature for 15 h and then partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (548 mg, 88%) as pale yellow crystals. MS 377 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19](O)[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[N:20]=1
Reactant: COc1ccc2c(O)nc(-c3ccc(OC(C)C)cc3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(OC(C)C)cc3)nc2c1
Yield: 80.1 %

Procedure:
A solution of 2-(4-isopropoxyphenyl)-7-methoxyquinazolin-4-ol (495 mg, 1.595 mmol) in POCl3 (2 ml, 21.46 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes. The product fractions were collected and the solvent was removed under vacuum to give 4-chloro-2-(4-isopropoxyphenyl)-7-methoxyquinazoline (420 mg, 80% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.59-8.53 (m, 2H), 8.11 (d, J=9.3 Hz, 1H), 7.24 (dd, J=9.2, 2.4 Hz, 1H), 7.04-7.00 (m, 3H), 4.70 (quin, J=6.0 Hz, 1H), 4.03 (s, 3H), 1.40 (d, J=6.0 Hz, 6H); MS: MS m/z 329.1 (M++1).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH:3]([CH3:6])[CH2:4][CH3:5].[CH3:14][N:15](C=O)C>O.[C-]#N.[Zn+2].[C-]#N>[OH:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:14]#[N:15])=[CH:9][CH:8]=1)[CH:3]([CH3:6])[CH2:4][CH3:5]
Reactant: CN(C)C=O
Reactant: CCC(C)C(O)c1ccc(Br)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCC(C)C(O)c1ccc(C#N)cc1
Temperature: 90 °C
Yield: 75 %

Procedure:
Add 4-(1-hydroxy-2-methyl-butyl)-1-bromo-benzene (1.9 g, 7.8 mmol), zinc cyanide (1.82 g, 15.6 mmol), and tetrakistriphenylphosphine palladium(0) (260 mg, 0.22 mmol) to anhydrous DMF (40 mL) under a nitrogen atmosphere. Heat the mixture at 90° C. for 12 h. Cool the mixture to room temperature, dilute with water and extract the aqueous phase twice with dichloromethane. Wash the combined organic extracts with water and brine. Dry the organic solution over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 20:1) to provide the desired intermediate (1.2 g, 75%). MS (APCI) m/z: 190 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][CH2:31][O:32][C:25]=3[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][CH2:31][O:32][C:25]=4[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.CN1CCOCC1.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[OH:43][C@@H:44]1[CH2:48][CH2:47][N:46]([C:49]2[C:57]([C:58]3[N:62](C4CCCCO4)[N:61]=[CH:60][CH:59]=3)=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][N:50]=2)[CH2:45]1>C1COCC1.O>[Cl:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:53](=[O:54])[C:52]2[CH:56]=[C:57]([C:58]3[NH:62][N:61]=[CH:60][CH:59]=3)[C:49]([N:46]3[CH2:47][CH2:48][C@@H:44]([OH:43])[CH2:45]3)=[N:50][CH:51]=2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Reactant: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Alternatively, Stage 9.1 was prepared by adding 4-(chlorodifluoromethoxy)aniline (16.6 g, 84.9 mmol), NMM (21.7 g, 212.1 mmol), hydroxybenzotriazole hydrate (HOBt.H2O, 11.9 g, 77.77 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 20.9 g, 109.0 mmol) to a solution of 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid (Stage 9.4, 29.83 g, 70.7 mmol) in THF (271 mL). The mixture was stirred for 1.5 h at 25° C. and then at 65° C. for 16 h. After cooling the RM to 35° C., further EDCI.HCl (13.3 g, 69.4 mmol) was added and the RM was stirred for 1.5 h at 35° C. then again at 65° C. for 16 h. After cooling the RM to 35° C., water (150 mL) was added, the THF was removed under reduced pressure, EtOAc (180 mL) was added and the mixture was stirred for at 35° C. for 1 h. The two layers were separated and the aq. phase was then extracted with EtOAc (60 mL). The combined organic layers were washed with water (90 mL), brine (90 mL). The solvent was evaporated off under reduced pressure to give a brown solid which was purified by column chromatography (Silica gel, DCM/MeOH 40:1 to 20:1) to afford the title compound as a yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:20][CH2:21][CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:23][CH2:22][CH2:21][CH2:20][N:14]1[CH2:13][CH2:12][C:11]2([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][NH:9][C:10]2=[O:17])[CH2:16][CH2:15]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Yield: 4 %

Procedure:
1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (5.00 g, 21.6 mmol, 1.00 equiv), 3-bromopropylamine hydrobromide (4.73 g, 21.6 mmol, 1.00 equiv) and potassium carbonate (2.99 g, 21.6 mmol, 1.00 equiv) were stirred in refluxing dioxane (70 mL) for 24 hours. After removal of the solvent, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1N aqueous NaOH. The mixture was extracted with CH2Cl2 (200 mL+3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3—MeOH—NH3 (2M in MeOH) 100:20:10 to 100:24:12) to give 250 mg (4%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=2)[N:6]=[C:5](Cl)[N:4]=1.[OH2:16].[CH3:17]O>>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([O:16][CH3:17])[N:4]=1
Reactant: CCc1ccc2nc(Cl)nc(N)c2c1
Reactant: O
Reactant: CO
Agent: [Na]
Product: CCc1ccc2nc(OC)nc(N)c2c1
Temperature: 60 °C

Procedure:
To a solution of sodium metal (1.19 g) in methanol (270 ml) was added 4-amino-2-chloro-6-ethylquinazoline (9.01 g). The reaction mixture was heated under reflux for 7 hours and heated for 38 hours at 60° C. The resultant mixture was concentrated under reduced pressure to give a residue, to which was added water under warming with stirring. The precipitates were separated by filtration and dried under reduced pressure to give crystalline 4-amino-6-ethyl-2-methoxyquinazoline (6.77 g).
Reaction SMILES: [S:1]1[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[C:10]1([NH:16]N)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH2:3]1[C:4]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:16][C:5]=2[CH2:6][CH2:7][CH2:8][S:1][CH2:2]1
Reactant: O=C1CCCSCCC1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: c1ccc2c3c([nH]c2c1)CCCSCC3

Procedure:
A mixture of 7.2g (0.05 mole) of 1-thiacyclooctane-5-one and 6.0g (0.056 mole) of phenylhydrazine in 40 ml of glacial acetic acid is refluxed for three hours under nitrogen. On standing there is deposited 5.2g of a solid, m.p. 106°-107° C. Recrystallization from cyclohexane affords 4.9g (45%) of an analytical sample m.p. 109°-110° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:4]=[N:3]1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]3[CH:28]=[C:29]([CH2:33]O)[CH:30]=[CH:31][CH:32]=3)=[N:25][CH:26]=2)[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[CH3:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[N:25][C:24]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[CH2:33][N:11]3[C:10](=[O:13])[CH:9]=[CH:8][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:12]3)=[N:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Reactant: Cn1cc(-c2ccc(=O)[nH]n2)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCN(c2cnc(-c3cccc(Cn4nc(-c5cnn(C)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
71 mg (0.40 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one and 163 mg (0.40 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}-methanol are suspended in 3 ml of THF and 1 ml of DMF with 200 mg (0.60 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and shaken at room temperature for 30 min. 139 mg (0.60 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 1 h. A further 200 mg (0.6 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and 139 mg (0.60 mmol) of di-tert-butyl azodicarboxylate are added, and the reaction mixture is shaken at room temperature for 2 h. The reaction mixture is filtered, the residue is evaporated, and the residue is purified by means of preparative HPLC; yield: 18 mg of “A286”; HPLC: Rt=2.08 min (method C); LC-MS: 443 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C:17]2[CH:25]=[CH:26][CH:27]=[C:15]([C:14]([F:13])([F:29])[F:28])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1

Procedure:
3-Amino-azetidine-1-carboxylic acid tert-butyl ester (AstaTech, 1.2 g, 6.97 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet Building Blocks, 1.57 g, 6.36 mmol) were treated with EDCI (Aldrich, 1.57 g, 6.36 mmol), HOBT (Aldrich, 1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, and purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f5) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=3)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]#[CH:32].O>CN(C)C=O>[O:1]=[C:2]1[N:7]([CH2:32][C:31]#[CH:30])[C:6]2[CH:8]=[C:9]([C:12]3[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=3)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc3c(c2)NC(=O)CO3)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2ccc(-c3ncc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Then, 0.15 g of 3-(3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-1) was dissolved in 0.92 ml of N,N-dimethylformamide, to which 0.127 g of potassium carbonate and 70 μl of propargyl bromide were added, and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.12 g (yield, 74%) of 3-(3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-13; m.p., 129.2° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH:45]3[CH2:47][CH2:46]3)=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH:45]3[CH2:46][CH2:47]3)=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(C4CC4)cc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K33) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (345 mg, 77%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[H][H].[CH2:60](Br)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O>[C:61]1([CH2:60][N:31]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:18]([C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCCN(CCCCCCCN(CCCCNS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccccc2)C(=O)c2ccccc2)cc1
Reactant: [H][H]
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCCCN(CCCCCCCN(CCCCN(Cc2ccccc2)S(=O)(=O)c2ccc(C)cc2)C(=O)c2ccccc2)C(=O)c2ccccc2)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Suspend sodium hydride (48 mg, 2 mmol) in anhydrous dimethylformamide (2 mL), cool to 0° C. and place under a nitrogen atmosphere. Add, by dropwise addition, a solution 1,19-bis[(4-methylphenyl)sulfonyl]-6,14-bis(benzoyl)-1,6,14,19-tetraazanonadecane (78 mg, 1 mmol) in dimethylformamide (2 mL). Stir until evolution of hydrogen ceases. Add, by dropwise addition, a solution of benzylbromide (34 mg, 2 mmol) in dimethylformamide (2 mL). Stir overnight at room temperature then carefully quench with saturated ammonium chloride. Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatogaphy to give the title compound.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-:47]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]([F:47])=[CH:2][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: [F-]
Reactant: CNC(=O)c1ccc(Br)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CNC(=O)c1ccc(C=C(F)n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 80 °C

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (268 mg, 1.2 mmol), 4-bromo-2-fluoro-N-methyl-benzamide (230 mg, 1.0 mmol), dichlorobistriphenyl phosphinepalladium (II) (21 mg, 0.03 mmol) and TBAF.3H2O (945 mg, 3.0 mmol) were added to a reaction vessel and the contents heated at 80° C. for 5 min in microwave. After completion of reaction (as monitored by TLC & LCMS), the reaction mixture was poured into water (25 mL) and the compound extracted with EtOAc (3×60 mL). The combined organic layers were dried over sodium sulfate, concentrated under vacuum and purified by reverse phase chromatography to obtain 22 mg of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-fluoro-vinyl]-2-fluoro-N-methyl-benzamide and 63 mg of product. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.80 (t, 1H), 7.55-7.42 (m, 3H), 7.36 (s, 1H), 7.18 (d, 1H), 6.20 (d, 1H), 4.75 (m, 2H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 2H), 3.18 (s, 3H), 2.94 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][NH2:14]>>[ClH:1].[CH2:8]([C:7]1[C:2]([NH:11][CH2:12][CH2:13][NH2:14])=[N:3][CH:4]=[N:5][C:6]=1[CH3:10])[CH3:9]
Reactant: CCc1c(C)ncnc1Cl
Reactant: NCCN
Product: CCc1c(C)ncnc1NCCN
Product: Cl
Temperature: 150 °C
Yield: 144.8 %

Procedure:
4-Chloro-5-ethyl-6-methylpyrimidin (570 mg, 4 mmol) was mixed with 1,2-diaminoethane (2 ml, 30 mmol) and stirred at 150° C. in a closed vessel under microwave heating. The mixture was evaporated to dryness under reduced pressure to yield 1.255 g of a solid. MS (APCI) m/z=181.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:9]=[O:10])=[CH:5][CH:4]=1.[BH4-].[Na+].O.CCOCC>C(O)(C)C>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[CH2:9][OH:10])=[CH:21][CH:22]=1
Reactant: O=CC(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)O
Product: OCC(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
(4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetaldehyde, 124 (0.02 mol) was dissolved in isopropanol (20 mL) and sodium borohydride (0.02 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ether were added. The organic phase was dried and concentrated, and the residue was chromatographed to afford the title compound 125. 1H-NMR (DMSO, 400MHz): δ 7.75-7.24 (m, 8H), 5.59 (μs, 1H), 5.22 (m, 1H), 3.70 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.CN.O[N:37]1[C:41]2C=CC=CC=2N=N1.CN1CCOCC1>O.CN(C)C=O>[CH3:41][NH:37][C:30]([C:29]1[C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A 50 mL round-bottom flask was charged with 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (0.43 g, 1.0 mmol), methylamine hydrochloride (0.14 g, 2.0 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.26 g, 1.4 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), N-methylmorpholine (0.4 mL, 3.6 mmol) and N,N-dimethylformamide (7 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 20 h, and poured into water (200 mL). The solid was collected by filtration, washed with water, dried and purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford N-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide (0.41 g, 92%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 7.20-7.07 (m, 2H), 6.95 (t, J=7.5, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.46 (d, J=1.2 Hz, 1H), 6.43 (d, J=1.2 Hz, 1H), 5.16 (ABq, 2H), 4.70 (ABq, 2H), 4.20-4.05 (m, 4H), 2.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 167.6, 154.9, 152.7, 150.1, 144.5, 143.3, 138.1, 136.2, 132.5, 131.6, 129.0, 123.7, 123.1, 122.9, 122.2, 112.4, 109.6, 99.0, 79.7, 64.6, 64.1, 57.7, 43.3, 26.5; MS (ES+) m/z 443.9 (M+1).