Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
10.0 g (46.3 mmol) of methyl 5-bromonicotinate and 10.6 g (55.5 mmol) of 3-trifluoromethylphenylboronic acid were reacted according to the General Method 1A. Yield: 11.9 g (91% of theory)
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]2[O:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[C:17]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH2:9][N:25]2[CH2:26][CH2:27][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[CH:14][NH:13]4)[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: Fc1ccc(OCC2CO2)cc1
Product: OC(COc1ccc(F)cc1)CN1CCN(c2cccc3[nH]ccc23)CC1
Yield: 99.3 %

Procedure:
A methanolic solution (50 ml) of 1-(4-fluorophenoxy)-2,3-epoxypropane (0.50 g, 3.0 mmole) and 1-(indol-4yl)-piperazine (0.6 g, 3.0 mmole) was refluxed for 1 hr under an atmosphere of nitrogen. The mixture was concentrated in vacuo, and the product purified by silica gel chromatography (EtOAc) to afford a white solid (1.1 g, 99%). Treatment with a 0.25M ethanolic fumaric acid solution gave the required salt, which was recrystallized from ethanol to afford the title compound as a white solid. m.p. 234-235° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.[Br:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH2:27][N-:28][CH3:29])=[CH:20]2.C(N(CC)CC)C>C(Cl)Cl>[Br:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH2:27][N:28]([CH3:29])[C:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=1)=[O:12])=[CH:20]2
Reactant: C[N-]Cc1ccc2c(Br)c(OC)ccc2c1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2cc(CN(C)C(=O)c3cn(C)c4ccccc34)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A solution of 1-methyl-1H-indole-3-carbonyl chloride (27 mmol), prepared in the previous step, in 50 mL of methylene chloride was added dropwise under nitrogen over 1.5 h to a solution of (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (7.56 g, 27 mmol), prepared in step 7 of Example 36, and triethylamine (3.76 mL, 27 mmol) in 200 mL of methylene chloride at room temperature. The solution was stirred at room temperature for 22 h (overnight). The reaction was extracted with 1N HCl. The aqueous layer was separated and extracted two additional times with methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give 11.52 g of an off white solid. The solid was recrystallized from methylene chloride-isopropanol. Off-white crystals were collected by filtration and dried under reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (9.3389 g, 79%) as an off white solid, mp 168-169° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[S:26][C:27]([N:30]=[C:31]=[O:32])=[CH:28][CH:29]=1.C(Cl)Cl.CO>C(Cl)Cl>[Cl:24][C:25]1[S:26][C:27]([NH:30][C:31]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:32])=[CH:28][CH:29]=1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: O=C=Nc1ccc(Cl)s1
Solvent: ClCCl
Solvent: CO
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)Nc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (the product of step (e) in Example 1) (98 mg, 0.307 mmol) was dissolved in 10 ml DCM. TEA (46 mg, 0.45 mmol) was added and the reaction mixture was flushed with Ar. 2-chloro-5-thienylisocyanate (58.8 mg, 0.368 mmol) was added on ice bath, and the resulting mixture was agitated at room temperature overnight. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, low boiling point solvent was evaporated under reduced pressure. Column chromatography (DCM/MeOH=100/1) afforded 87 mg white solid, yield: 59.2%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)[C:4]=2[CH:3]=1.[CH2:18]([C:20]1[N:25]=[C:24]([Sn](C)(C)C)[CH:23]=[N:22][CH:21]=1)[CH3:19]>CN(C)C(=O)C.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>[CH2:18]([C:20]1[N:25]=[C:24]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=4)[C:4]=3[CH:3]=2)[CH:23]=[N:22][CH:21]=1)[CH3:19]
Reactant: Fc1cccc(-n2ncc3cnc(Cl)cc32)n1
Reactant: CCc1cncc([Sn](C)(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)n1
Temperature: 150 °C
Yield: 41.3 %

Procedure:
To a solution of 6-chloro-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (85 mg; 0.34 mmol) and tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol) in N,N-dimethylacetamide; 2.0 mL was added (6-ethylpyrazin-2-yl)-trimethyl-stannane (185 mg, 0.684 mmol). The reaction was purged with N2 for 5 min then heated at 150° C. for 45 min in biotage microwave. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc then washed with water. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 50% EtOAc) to give 6-(6-ethylpyrazin-2-yl)-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (45 mg) in 41% yield. MS (ESI) m/z: 321.2
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([OH:21])[CH:13]=1.[C:22](=O)([O:25]C)[O:23][CH3:24].Cl>O1CCCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:22]([O:23][CH3:24])=[O:25])=[C:14]([OH:21])[CH:13]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(F)cc1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(F)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A 1.0 M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (39.0 mL, 39.0 mmol) was stirred at −78° C. and treated over a 25 min period with a solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (2.00 g, 13.0 mmol) in 50 mL of tetrahydrofuran. The resulting solution was stirred at −78° C. for 1 h, and then at −15° C. for 2 h. After being cooled again to −78° C., the solution was treated with a solution of dimethyl carbonate (1.20 mL, 14.3 mmol) in tetrahydrofuran (5 mL). The resulting mixture was allowed to warm to rt where it stirred overnight. After this time, the mixture was poured over ice and then concentrated hydrochloric acid (10 mL) was added. The resulting mixture was extracted three times with dichloromethane. The combined organic phases were washed twice with water, dried over sodium sulfate and then concentrated under vacuum to yield a residue. The residue was purified by radial thin-layer chromatography (silica gel, 2-40% ethyl acetate-hexane) to provide methyl 3-(4-fluoro-2-hydroxyphenyl)-3-oxopropanoate as a white solid (1.76 g, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 3.98 (s, 2 H) 6.62-6.71 (m, 2 H) 7.69 (dd, J=8.9, 6.4 Hz, 1 H) 12.15 (d, J=1.5 Hz, 1 H). Mass spectrum m/z 213.14 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH2:38])=[CH:31][CH:30]=1)[CH3:21]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1)[CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccccc1Oc1ccc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 171.7 %

Procedure:
In a 50 mL round-bottomed flask N-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 78, 67.1 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (13.28 mg, 0.109 mmol), triethylamine (0.076 mL, 0.544 mmol) and triphosgene (32.3 mg, 0.109 mmol) were added. The reaction mixture was stirred at 0° C. After 20 minutes, the reaction mixture was evaporated under vacuum to afford a yellow solid which was purified by silica gel chromatography (Biotage system, 10 g SNAP column) eluting with a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a white solid (60.9 mg).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][CH:9]([F:12])[CH2:10][OH:11].F[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[S:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=2>O>[F:8][CH:9]([F:12])[CH2:10][O:11][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[S:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[CH:24][N:23]=2
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a mixture of 51 mg of sodium hydride (60% dispersion in mineral oil) and 2 ml of DMF was added at room temperature a mixture of 0.10 g of 2,2-difluoro-ethanol and 1 ml of DMF. This mixture was stirred at room temperature for 15 minutes, then, cooled with ice. Next, to this was added a mixture of 0.29 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine and 10 ml of DMF, and the resultant mixture was stirred for 0.5 hours under ice cool, further for 0.5 hours at room temperature. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.27 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 13).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([OH:18])=O)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.S(Cl)([Cl:21])=O>ClCCl>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([Cl:21])=[O:18])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CN1c2ccccc2C(C(=O)O)c2ccccc21
Solvent: ClCCl
Product: CN1c2ccccc2C(C(=O)Cl)c2ccccc21

Procedure:
A solution of 0.35 parts of 10-methylacridan-9-carboxylic acid (77) in 20 mL dichloromethane and 1.1 parts of thionyl chloride is treated as described in Example I, to give 10-Methylacridan-9-carboxylic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:16][C@H:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: O[C@H]1CCOC1
Reactant: N#Cc1cnc(N)cc1F
Product: N#Cc1cnc(N)cc1O[C@H]1CCOC1

Procedure:
From intermediate 21 and (S)-tetrahydrofuran-3-ol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.48 min; ESI-MS 206.1 [M+H]+.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[N:3]([O:2][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2nccn2O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Product: COc1ccc(-c2nccn2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-2-(4-methoxyphenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (89%, crystals).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[C@@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:35][S:32]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:24]=1[CH:6]1[N:5]([S:37]([CH3:36])(=[O:39])=[O:38])[C:4](=[O:3])[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]1=2)[C:28]#[N:29])(=[O:33])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 20 mg, 0.50 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 100 mg, 0.18 mmol based on 85% purity) in tetrahydrofuran (4.0 mL), and the mixture is stirred at room temperature for 20 min Methanesulfonyl chloride (29 μL, 0.38 mmol) is added and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is extracted with dichloromethane. The phases are separated and the organic layer is concentrated under a) reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 76 mg; ESI mass spectrum [M+H]+=554; Retention time HPLC: 0.57 min (X012_S01).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:22]>>[ClH:22].[CH3:21][O:20][CH2:19][CH2:18][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: COCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: COCCOc1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-(2-methoxy-ethoxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. White solid. MS (m/e): 194.3 ([M+H]+, 100%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[C:15]([C:27]([F:30])([F:29])[F:28])[CH:14]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(CC)CC.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>[Cu]I.CN(C=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[C:15]([C:27]([F:30])([F:28])[F:29])[CH:14]=2)=[O:11])=[CH:3][C:2]=1[C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
The product (1.06 g, 2.0 mmol) obtained from Step 1, CuI (0.19 g, 0.1 mmol), Pd(PPh3)Cl2 (0.35 g, 0.5 mmol) and DMF (10 ml) were added into a 100 ml three-necked flask, and Et3N (0.52 g, 4.0 mmol) and trimethylsilylacetylene (0.98 g, 10 mmol) were added under the protection of an inert gas atmosphere. The mixture was reacted at 80° C. for 16 hours with stirring, and the system was cooled to room temperature, filtered, and extracted with ethyl acetate (50 ml×3) and H2O (50 ml). The organic phases were back-extracted with saturated brine, and the organic phases were combined, dried over anhydrous Na2SO4, and purified by column chromatography, to give a milky white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Reactant: C1COCCN1
Solvent: CO
Product: N#CC1(N2CCOCC2)CCN(Cc2ccccc2)CC1

Procedure:
A solution of 5.25 g (23.8 mmol) 1-benzyl-4-hydroxy-piperidine-4-carbonitrile and 2.2 mL (25.2 mmol) morpholine in 30 mL MeOH was refluxed for 6 h. The mixture was evaporated to dryness i.vac., while the product was obtained in the form of crystals.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([F:30])[CH:18]=2)=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-].O>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([F:30])[CH:18]=2)=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Ethyl 2-[2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (385 mg, 0.89 mmol, 1.0 eq) in THF (4 mL) was added an aqueous solution of LiOH (2M aqueous solution, 3 mL, 6 mmol, 6.7 eq). The reaction was stirred at room temperature for 1 h. Water was added and the THF removed in vacuo. The aqueous residue was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude material obtained was recrystallised from DCM/petroleum ether, collected by filtration and dried in vacuo to give (I(n)) (60 mg, 17%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]2[C:12]3[N:13]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:14]=[C:15]([CH3:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(OCC)(=O)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([C:11]2[C:12]3[N:13]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:14]=[C:15]([CH3:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: CCOC(=O)c1c(C)nn2c(CC)ccc2c1-c1ccc(C(=O)O)c(Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nn2c(CC)ccc2c1-c1ccc(CO)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
To a solution of 2-bromo-4-[3-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzoic acid (50.0 mg) in tetrahydrofuran (1 mL) was added a solution of 1 M borane-tetrahydrofuran complex (0.348 mL) in an ice bath. After stirring for 2 hours at room temperature, additional solution of the borane-tetrahydrofuran complex (0.348 mL) was added. The mixture was stirred for 15 hours at room temperature. The mixture was parititioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give ethyl 4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil (54.2 mg).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O>CO>[CH3:30][C:29]1([CH3:32])[O:31][CH2:16][CH2:15][N:14]([S:11]([C:8]2[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CC(C)(C)O)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
Sodium methoxide (9.7 g) was added to a stirred solution of 1-{N-[(4-methylphenyl)sulfonyl]-N-[(4-methylphenyl)sulfonyloxyethyl]amino}-2-methyl-2-propanol (72.2 g) in methanol (350 ml) and the solution was stirred at room temperature for 1.5 h. A further amount of sodium methoxide (9.7 g) was then added and the mixture was stirred for an additional 30 min. The suspension was poured into water (1.2 l) and the mixture was stirred for 20 min. The colourless solid was filtered off, washed with water and dried in vacuo at 60° C. to give 2,2-dimethyl-4-[(4-methylphenyl)sulfonyl]morpholine (41.0 g). m.p. 95°-97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[C:14]([C:18]([C:23]2[N:24]=[CH:25][N:26]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[CH:17]=[CH:12][CH:13]=[C:14]([C:18]([C:23]3[N:24]=[CH:25][N:26]([C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:27]=3)([OH:22])[CH:19]([CH3:20])[CH3:21])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1cccc(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 68.4 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 4-fluorophenylboronic acid (0.41 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.01 g), the title compound (0.71 g) was obtained as a pale-yellow solid.
Reaction SMILES: [N:1]1[NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][C:11]4=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=[C:10]4[C:9]=1[C:8]=23.[CH:19]1([C:22](O)=[O:23])[CH2:21][CH2:20]1>>[N:1]1[NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][C:11]4[C:14]([NH:18][C:22]([CH:19]5[CH2:21][CH2:20]5)=[O:23])=[CH:15][CH:16]=[CH:17][C:10]=4[C:9]=1[C:8]=23
Reactant: Nc1cccc2c1CCc1cccc3[nH]nc-2c13
Reactant: O=C(O)C1CC1
Product: O=C(Nc1cccc2c1CCc1cccc3[nH]nc-2c13)C1CC1

Procedure:
6,7-Dihydro-2H-benzo[6,7]cyclohepta[cd]indazole-8-amine prepared in Example 8 and cyclopropanecarboxylic acid were subjected to the reaction and purified and separated by LC-MS in the same manner as in Synthesis Process A, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:21]([CH:22]([CH3:24])[CH3:23])[C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:22]([N:21]1[C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=[C:2]1[NH:1][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:23])[CH3:24]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(N)n3C(C)C
Reactant: O=C(Cl)c1ccccc1
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(NC(=O)c1ccccc1)n3C(C)C
Yield: 67.9 %

Procedure:
The compound (170 mg) is prepared from D6 (190 mg) and benzoyl chloride (0.2 ml; 1.60 mmol) as described in Example 174.