Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:54][CH2:55][C@H:56]([OH:58])[CH3:57]>O.CN(C)C=O>[OH:58][C@H:56]([CH3:57])[CH2:55][NH:54][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C[C@@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@@H](C)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), (2R)-1-aminopropan-2-ol (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (220 mg, 65%) as colorless prisms. MS 519 (MH+). mp 185-186° C.
Reaction SMILES: COCCC(Cl)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]([CH2:27][CH2:28][O:29][CH3:30])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1.B1([C:37]2[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=2)OCCCO1>>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]([CH2:27][CH2:28][O:29][CH3:30])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1.[CH3:30][O:29][CH2:28][CH2:27][C:21]1[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[CH:18][C:17]=3[N:16]=[C:15]([NH2:19])[C:14]=2[N:20]=1
Reactant: c1cncc(B2OCCCO2)c1
Agent: COCCC(=O)Cl
Agent: COCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: COCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was prepared according to the procedures described in Parts A and B of Example 9 using methoxypropanoyl chloride instead of ethoxyacetyl chloride. 7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with pyridine-3-boronic acid 1,3-propanediol cyclic ester according to the method described in Examples 118–121. The reaction was heated at reflux overnight, and the work-up procedure described in Part F of Examples 125–131 was followed. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 76:24) followed by recrystallization from methanol. The crystals were dried at 1.33 Pa and 98° C. to provide 2-(2-methoxyethyl)-1-(2-methylpropyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white needles, mp 207–208° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.[F:18][C:19]([F:33])([CH3:32])[CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][OH:23].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:18][C:19]([F:33])([CH3:32])[CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:22][O:23][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: CC(F)(F)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2cnccc2c2ccc(OC[C@H](CC(C)(F)F)NC(=O)OC(C)(C)C)cc21
Temperature: 85 °C
Yield: 22 %

Procedure:
In a sealed tube containing 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (30 mg, 0.123 mmol) and (S)-tert-butyl (4,4-difluoro-1-hydroxypentan-2-yl)carbamate (35.2 mg, 0.147 mmol) was added toluene (3 mL). Di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (31.2 mg, 0.074 mmol) and cesium carbonate (59.9 mg, 0.184 mmol) were added to the reaction mixture followed by palladium (II)acetate (8.26 mg, 0.037 mmol). The reaction mixture was then heated at 85° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through diatomaceous earth (Celite®), eluting with ethyl acetate. The filtrate was evaporated under reduced pressure and the crude product was purified by silica gel chromatography to afford (S)-tert-butyl (4,4-difluoro-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (12 mg, 0.027 mmol, 22% yield) as yellow solid. LC/MS (ESI) m/e 448.3 [(M+H)+, calcd for C23H28F2N3O4 448.2]; LC/MS retention time (method E): tR=0.96 min.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC=CC=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42](Cl)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:54]([C:56]1[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=1[F:63])#[CH:55]>>[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42]([C:55]#[C:54][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=2[F:63])=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Product: Fc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c(F)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-2,4-difluorobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added butyryl chloride (19.6 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MEOH and EtOAc/hexanes (1:1) to afford the title compound (46.2 mg, 73%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[CH2:32][OH:33]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH2:32][OH:33])[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: OC[C@H]1COCCN1
Product: COC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 53.3 %

Procedure:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.98 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.56 g, 53%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:32](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.CO>C(Cl)Cl>[CH3:32][O:24][C:23](=[O:25])[CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:17]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCn1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, methanol (20 μL, 0.49 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 3-{3-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid methyl ester (28 mg, 55%) as a white solid: ESI-LRMS m/e calcd for C22H28ClN3O5S [M+] 481.1, found 482.5 [M+H+]; 1H NMR (400 MHz, CDCl3), δ ppm 1.08-1.21 (m, 2H, CH2), 1.40-1.95 (m, 8H, 4×CH2), 2.13-2.28 (m, 1H, CH), 2.82 (t, J=6.5 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.6 Hz, 1H, CH), 3.67 (s, 3 H, CO2CH3), 4.27 (t, J=6.5 Hz, 2H, NCH2), 6.62 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.89 (s, 1H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1.CCN(C(C)C)C(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][N:14]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a slurry of 6-bromo-4-((3S,4S)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide salt from Step 1 of Example 158 (500 mg, 1.073 mmol) and DIPEA (0.562 mL, 3.22 mmol) in DCM (5 mL) at 0° C. was added a solution of methanesulfonyl chloride (160 mg, 1.395 mmol) in 1 mL of DCM dropwise and the resulting mixture was stirred at rt for 1 h. The reaction was quenched by addition of MeOH (˜1 mL) and was then concentrated to afford a solid which was suspended in water, stirred for 30 min. and collected by vacuum filtration and dried under vacuum to afford 380 mg (85%) of the title compound. HPLC (method B) retention time 2.75 min. LCMS (m+1)=416/418 (1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH2:6][CH2:5]2.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:5]2
Reactant: N#Cc1cccc(CN2CCc3cc(Cl)ccc32)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1cccc(CN2CCc3cc(Cl)ccc32)c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 4.41 g (16.4 mmole) of α-(5-chloro-1-indolinyl)-m-tolunitrile of Example 17a in 30 ml distilled THF was added dropwise over 30 minutes to a rapidly stirred ice cold slurry of 2.49 g (65.6 mmole, 4.0 equivalents) LiAlH4 in 65 ml distilled THF under nitrogen. After warming to room temperature, the mixture was heated under reflux for 2.75 hours, cooled in an ice bath, and quenched by dropwise addition of 2.5 ml water, 2.5 ml 10% NaOH, and 7.5 ml water. The salts were filtered and washed with 250 ml boiling methylene chloride. The filtrate was concentrated and the residue was dissolved in methylene chloride (100 ml), washed with brine (250 ml), dried over K2CO3, and concentrated to give 4.29 g (95.9%) of crude free base. The free base (4.23 g, 15.5 mmole) was dissolved in 30 ml absolute ethanol and added to a warm solution of 1.80 g (15.5 mmole) fumaric acid in 80 ml absolute ethanol. The fumarate salt slowly crystallized upon cooling to room temperature, thus affording 5.12 g (84.9%) of 3-(5-chloro-1-indolinylmethyl)benzenemethanamine fumarate, m.p. 178° C., dec.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(COC)OC.C[Si]([C:21]([F:24])([F:23])[F:22])(C)C.[F-].[Cs+]>CCCCCC.ClCCl>[F:22][C:21]([F:24])([F:23])[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnccn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCCCCC
Product: O=C(c1cnccn1)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of pyrazine carboxylate methyl ester is dissolved in an inert solvent, for example monoglyme (dimethoxyethane). To this solution is added a mixture of trimethylsilyltrifluoromethane and dry caesium fluoride. After about 12-24 hours, at a temperature of about room temperature, the solvent is removed under reduced pressure. The residue is dissolved in a mixture of an inert solvent, for example tetrahydrofuran, and an organic acid, for example acetic acid, and the mixture is treated with tert-butylammonium fluoride. The reaction is conducted at a temperature of about room temperature for about 3 hours. When the reaction is substantially complete, the compound of formula (18) is isolated by conventional means, for example by diluting with water, extracting the product into an inert solvent, for example ethyl acetate, washing with a solution of a mild inorganic base, for example sodium bicarbonate, and drying. Removal of the solvent under reduced pressure provides a crude compound, which can be purified by trituration with an inert solvent, for example a mixture of dichloromethane and hexane, to give a compound of formula (18), 2,2,2-trifluoro-1-(pyrazin-2-yl)ethanone.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:17]1[C:29]2[N:28]([C:30]3[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1.COCCOC.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(C)C=CC=CC=1>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:30]([N:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:21]4[C:29]3=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:31][CH:32]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: Ic1ccc(-c2nc3ccccc3o2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: c1ccc2oc(-c3ccc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)cc3)nc2c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
In a 100 mL three-neck flask were put 1.0 g (3.1 mmol) of 2-(4-iodophenyl)benzoxazole, 0.90 g (3.1 mmol) of 4-(9H-carbazol-9-yl)phenylboronic acid, and 0.067 g (0.22 mmol) of tri(ortho-tolyl)phosphine. To this mixture were added 30 mL of 1,2-dimethoxyethane (abbreviation: DME) and 30 mL of a 2M potassium carbonate aqueous solution. This mixture was degassed under reduced pressure, and then the atmosphere in the flask was replaced with nitrogen. To this mixture was added 7.0 mg (0.031 mmol) of palladium(II) acetate, and the resulting mixture was stirred at 90° C. for 5 hours while being heated. After that, toluene was added to this mixture, and the organic layer was washed with a saturated aqueous sodium carbonate solution and saturated brine in that order. After that, magnesium sulfate was added to the organic layer to dry it. Next, this mixture was suction filtered. The resulting filtrate was suction filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The resulting filtrate was concentrated, followed by purification by silica gel column chromatography. As a developing solvent for the chromatography, toluene was used. The fraction obtained was concentrated to give a solid. This solid was recrystallized with a mixed solvent of chloroform and methanol to give 1.2 g of a white powdered solid in a yield of 88%.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>CN(C)C=O.O>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:16][C:15]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=2[F:7])=[CH:27][CH:26]=1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: O=Cc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(F)c1
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
Potassium tert-butoxide (198 mg, 1.76 mmol) was added, at 0° C., to a solution of 3-Fluoro-4-hydroxy-benzaldehyde (235 mg, 1.68 mmol) in dry N,N-dimethylformamide (2 mL). The mixture was stirred for 10 minutes. 4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (539 mg, 1.84 mmol) was added and the reaction was stirred for 24 hours at room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (4×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under vacuum to produce a solid which was washed with hexanes to produce 4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-benzaldehyde as a pale brown solid (490 mg, 83%). 1H-NMR (CDCl3, 200.15 MHz): δ 9.83 (d, 1H, J=2.2), 7.64–7.23 (m, 9H), 7.09 (t, 1H, J=8.2), 6.96 (d, 2H, J=8.8), 4.32 (t, 2H, J=5.9), 4.21 (t, 2H, J=5.9), 2.35 (qn, 2H, J=5.9).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:3]=2)[CH2:17]1
Reactant: C1CNCCN1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(N3CCNCC3)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
The mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinoline (150.0 mg, 0.33 mmol), copper(I) iodide (20.0 mg, 0.1 mmol), piperazine (283.4 mg, 3.3 mmol), N,N-dimethylglycine hydrochloride (34.0 mg, 0.24 mmol) and potassium carbonate (110.0 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL). was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 4,4-dimethyl-6-(morpholine-4-sulfonyl)-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline (51.1 mg, 33.0%) as a white solid: MS (ESI) M+1=471.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[Cl:12])[CH3:2].[CH:14]1(B(O)O)C[CH2:15]1>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]2[CH2:15][CH2:14]2)[C:6]=1[Cl:12])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1ccnc(C)c1Cl
Product: CCOC(=O)c1ccnc(C2CC2)c1Cl

Procedure:
This compound was prepared using a method analogous to that of 3-chloro-2-methylisonicotinic acid ethyl ester (A.2.5.2), cyclopropylboronic acid replacing trimethylboroxine. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (9/1) gives the desired product as colorless oil;
Reaction SMILES: [C:1]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][O:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[N:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].CNN>O1CCCC1>[NH2:14][O:13][CH2:12][C:10]1[N:11]=[C:7]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:8][CH:9]=1
Reactant: CCCCC#Cc1nc(CON2C(=O)c3ccccc3C2=O)cs1
Agent: CNN
Solvent: C1CCOC1
Product: CCCCC#Cc1nc(CON)cs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
To a solution of 2-{[2-(hex-1-yn-1-yl)-1,3-thiazol-4-yl]methoxy}-1H-isoindole-1,3(2H)-dione (13.6 g, 40.1 mmol) in tetrahydrofuran (250 mL) was added methylhydrazine (3.69 g, 80.1 mmol) dropwise. After stirring 20 h at room temperature, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with water and the organic layer drid (MgSO4) and concentrated in vacuo. Purification on silica gel afforded 4-[(aminooxy)methyl]-2-(hex-1-yn-1-yl)-1,3-thiazole as a colourless oil [8.15 g, yield 94%; HPLC/MS: m/z=211 (M+H); log P(HCOOH)=1.76].
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH2:15][OH:16]>C1COCC1.C(Cl)(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: CC(C)(C)c1cc2ncc(CO)c(N)n2n1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2ncc(C=O)c(N)n2n1

Procedure:
A solution of (7-amino-2-tert-butylpyrazolo[1,5-a]pyrimidin-6-yl)methanol (380 mg, 1.73 mmol, 1 eq.) and MnO2 (1.5 g, 17.25 mmol, 10 eq.) in THF (6 mL) and CHCl3 (12 ml) was stirred for about 36 h at 25° C. under nitrogen. MnO2 was filtered and washed with 15% MeOH in CHCl3 (˜100 mL) and 30% MeOH in CHCl3 (˜100 mL) until no additional product was observed through analysis of the filtrates by TLC. The filtrates were combined and concentrated under vacuum to give Compound [CCXXXVII] as a yellow solid: LCMS (m/e) 219 (M+H); 1H NMR (300 MHz, DMSO, δ, ppm) 9.87 (s, 1H), 8.99-8.82 (s, 2H), 8.50 (s, 1H), 6.52 (s, 1H), 1.38 (s, 9H).